Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 3654264 | Hemoglobin Hobart or alpha 20(Bl)His----Arg: a new alpha chain hemoglobin variant. | 1987 | A new alpha chain hemoglobin variant, Hb Hobart, alpha 20(Bl)His----Arg, was detected in a 60-year-old female of British nationality. The proposita had a history of severe rheumatoid arthritis and had been treated for many years for a refractory microcytic anemia and/or iron deficiency. A hemoglobin electrophoresis screen indicated the presence of a hemoglobin variant, with electrophoretic characteristics similar to a Hb Lepore. However, the level of the variant (17.9%) and the presence of a minor variant Hb A2 band (0.4%) suggested that further investigation was indicated. The variant hemoglobin was purified by column chromatography and the alpha chain subjected to aminoethylation and tryptic digestion. Peptide mapping and amino acid analysis indicated that the histidine residue 20 had been substituted by an arginine residue. The substitution in Hb Hobart is at the first residue in the B Helix of the alpha chain of hemoglobin. As this is an externally placed amino acid in the hemoglobin molecule, a substitution at this position of the hemoglobin molecule would not be expected to cause any functional problems. A family study has shown that at least three other relatives are heterozygous for Hb Hobart. These family members have normal hematological findings. | |
| 3643217 | Binding sites for elastase on cultured human fibroblasts that do not mediate internalizati | 1987 Jan | The proteolytic actions of elastases have been implicated in extracellular matrix damage, which is characteristic of a variety of pathological conditions including emphysema and rheumatoid arthritis. In order to elucidate the molecular events involved in elastase interaction with connective tissue cells, the present study was designed to investigate the association of elastase with human fibroblasts at 4 degrees C. Elastase bound saturably to binding sites that were present on the surface of these cells. Analysis of cell-bound elastase by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the presence of a high molecular weight complex (Mr 54,000) that was not formed with elastase whose catalytic site serine was derivatized with a diisopropylphosphate group. The complex did not represent elastase bound to either protease nexin or contaminating serum. The cellular component with which elastase formed a complex could not be detected in the cell culture medium. Unexpectedly, elastase that had been pre-bound at 4 degrees C was not internalized after cells were warmed to 37 degrees C. The elastase binding site described in this report is therefore distinct from high affinity binding sites involved in receptor-mediated endocytosis and intracellular degradation. | |
| 3783029 | Iron binding, internalization, and fate in human alveolar macrophages. | 1986 Dec | Chronic inflammation in such diseases as rheumatoid arthritis has been associated with the accumulation of iron in mononuclear phagocytes. Cigarette smoking, which also produces chronic pulmonary inflammation, may be associated with iron accumulation in alveolar macrophages (AM). We have examined the total iron content in human AM and found it to be 43.0 +/- 7.7 (mean +/- SEM) and 12.8 +/- 1.3 nmol/1 X 10(6) cells (P less than 0.01) from smokers and nonsmokers, respectively. Because the higher iron content in smokers' macrophages may reflect increased internalization, the binding and uptake of iron-saturated transferrin was examined in cells from smokers and nonsmokers. However, no significant differences were found between the two groups. The smoking-related alteration in iron content may instead reflect differences in the fate of internalized iron. Iron internalized by AM as iron 59 initially bound to transferrin was distributed to a cytoplasmic, largely ferritin-associated, pool more slowly in smokers than in nonsmokers, during a 24-hour incubation in vitro. Significantly less newly internalized iron was returned to the culture medium by AM from smokers, which by 24 hours had released 11.0% +/- 3.7% of the initially internalized 59Fe compared with 36.0% +/- 2.3% for nonsmokers (P less than 0.01). The increased accumulation of iron by AM in the alveolar space of smokers may modulate hydroxyl radical production in the microenvironment of these cells. | |
| 1767343 | [Relationship between serum interleukin-4 or interferon-gamma level and B cell abnormality | 1991 Oct | The role of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in the pathogenesis of the collagen vascular diseases was studied. The serum level of IL-4 was decreased in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), and was variable in patients with rheumatoid arthritis (RA). The serum level of IFN-gamma was increased in patients with SLE, MCTD and RA. In patients with SLE, there was an inverse correlation between the levels of IL-4 and IFN-gamma. The proliferation and immunoglobulin production of the high-density-B cells in response to IL-4 was suppressed in normal controls, although the degree of suppression was less in patients with SLE. Cell cycle analysis using ethidium bromide demonstrated the similar findings. These data suggest that IL-4 and IFN-gamma might participate in regulating both of growth and differentiation of B cells in vivo. However, immunoglobulin production by whole B cells in response to IL-2 or PHA-induced T-cell factor was extensively facilitated by IFN-gamma in patients with SLE. It is possible that IFN-gamma enhances the differentiation of already-activated B cells, and that polyclonal B cell activation is promoted. Therefore, the failure of the regulatory mechanism by these cytokines might be related to the pathogenesis of these diseases. | |
| 2147105 | Inherited complement deficiency states: implications for immunity and immunological diseas | 1990 Oct | The study of complement deficiency states and their influence on immune function has generated new insights and still provides a challenge to continued investigation. The association of classical pathway deficiencies (C1, C4, C2 or C3) with immunological diseases such as SLE and glomerulonephritis has contributed to current knowledge concerning complement-dependent immune complex handling and elimination. Susceptibility to systemic infection with encapsulated bacteria is encountered in most forms of inherited complement deficiency. Recurrent neisserial infection is the only clinical manifestation clearly associated with defects of the membranolytic sequence C5-C9, while deficiency of properdin, a component of the alternative activation pathway, appears to predispose to nonrecurrent meningococcal disease. Inherited complement deficiency is rare, but the perspective is widened by the more common occurence of acquired defects in immunological diseases, and the apparent requirement for efficient complement recruitment in host defense. Another aspect is the possibility that complement deficiency might alleviate or prevent inflammatory symptoms. Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients. | |
| 2141541 | Bronchial asthma is not associated with auto-antibodies to lipocortin-1. | 1990 Mar | Corticosteroids may mediate some of their anti-inflammatory action by the induction of lipocortin-1, which inhibits phospholipase A2 activity. Raised levels of antibodies to lipocortin have been found in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and it has been postulated that these may contribute to steroid resistance. A proportion of asthmatic patients fail to respond to treatment with corticosteroids and one possible mechanism is that these patients have raised levels of anti-lipocortin antibodies. We have therefore measured IgG and IgM antibodies to lipocortin by enzyme linked immunosorbent assay (ELISA) in eight corticosteroid-sensitive (CS) and 7 corticosteroid-resistant (CR) asthmatic subjects, and in eight normal controls. Comparison of asthmatic subjects with normal controls revealed no significant differences in either IgG or IgM antibodies to lipocortin. Comparison of CS asthmatic subjects with CR asthmatic subjects similarly revealed no significant differences in the concentration of either IgG or IgM antibodies to lipocortin. Levels of anti-lipocortin antibodies did not correlate with clinical response to treatment with 40 mg/day of prednisolone. Anti-lipocortin antibodies are unlikely to be involved in the inflammation seen in asthma, or in the relative insensitivity to corticosteroids seen in CR asthmatic subjects. | |
| 2129778 | Autoantibodies to poly(ADP-ribose)polymerase in autoimmune diseases. | 1990 | Antibodies to various nuclear proteins are frequently found in sera of patients affected by connective tissue diseases and other autoimmune diseases. We investigated the specificity of circulating autoantibodies to poly(ADP-ribose)polymerase (pADPRP) in different autoimmune and connective tissue diseases: Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Progressive Systemic Sclerosis (PSS), Sjogren's Syndrome (SS), Undifferentiated Connective Tissue Disease (UCTD), Cryptogenic Fibrosing Alveolitis (CFA) and Sarcoidosis. pADPRP was purified from calf thymus. Antibody specificity was detected by ELISA, western blot and enzyme activity precipitation. Positive values (mean O.D. values + 3 S.D. of 36 normal controls) were obtained in 7/15 SLE patients, 1/18 RA patients, 1/30 PSS, 3/14 SS, 0/5 UCTD, 5/21 CFA and 4/25 Sarcoidosis. The positive sera also recognized the pADPRP protein when tested by western blot. Furthermore the enzyme activity was inhibited after immunoprecipitation by some highly positive sera. | |
| 2478889 | Ionomycin-regulated phosphorylation of the myeloid calcium-binding protein p14. | 1989 Nov 9 | Two associated calcium-binding proteins (CaBPs) have recently been identified specifically in cells of myeloid origin. These proteins have relative molecular masses (Mr) of 8,000 and 14,000 and are variously referred to as the cystic fibrosis antigen, the L1 light chain, MRP-8 or p8, and the L1 heavy chain, MRP14 or p14, respectively. The expression of p8 and p14 seems to be confined to a specific stage of myeloid cell differentiation, because both proteins are expressed in circulating neutrophils and monocytes but not in normal tissue macrophages. In chronic inflammatory conditions, however, such as rheumatoid arthritis, macrophages in affected tissues express both p8 and p14. These proteins are members of a family of CaBPs of low Mr, which include S-100 alpha and beta proteins, calcyclin (2A9), intestinal CaBP and p11. All the proteins have an Mr of approximately 10,000 with the exception of p14 which has a longer C-terminal sequence after the second calcium-binding domain. Little is known about their function, although by analogy with calmodulin they could be molecules involved in intracellular signalling that are activated by an increase in the intracellular Ca2+ concentration ([Ca2+]). Here we report that p14 is phosphorylated in both monocytes and neutrophils. The level of p14 phosphorylation can be increased by elevating the [Ca2+]i using the ionophore ionomycin, but is not affected by activation of protein kinase C using phorbol 12,13-dibutyrate. The phosphorylated residue is threonine at position 113, which is the penultimate amino acid in p14 and contained in the longer 'tail' sequence. Part of this sequence is identical to the neutrophil immobilizing factors NIF-1 and NIF-2, indicating that the phosphorylation event could have a role in the generation of NIF activity in the p14 protein. | |
| 2515017 | Inhibitory effects of gold sodium thiomalate on DNA polymerase alpha. | 1989 Nov | The usefulness of gold compounds in the therapy of rheumatoid arthritis is well established, however, the pharmacological mechanisms of the compounds are still unclear. In this report, effects of gold compounds on DNA synthesis were examined. Gold sodium thiomalate inhibited DNA synthesis in the HeLa "nuclei system" as well as in the enzyme reaction using DNA polymerase alpha. More precisely, gold sodium thiomalate inhibited the activity of DNA polymerase alpha using activated DNA, poly[d(A-T)] or poly[d(G-C)] for the template, but did not inhibit the activity of DNA polymerase I with each template. The compound had also no inhibitory effect on DNA polymerase beta or gamma. On the other hand, auranofin inhibited the incorporation of [3H]thymidine into HeLa DNA but did not inhibit DNA synthesis in the HeLa "nuclei system". The inhibition of DNA polymerase alpha activity by gold sodium thiomalate was competitive with poly(dA).oligo(dT) for template but noncompetitive with dTTP. Thus, gold sodium thiomalate is a potent and specific inhibitor of DNA polymerase alpha and this inhibitory effect could play an important role in the therapeutic and pharmacological effects of gold sodium thiomalate. | |
| 3208135 | Detection of novel proteins associated with secondary amyloidosis and Alzheimer's disease | 1988 Dec 6 | We have established a monoclonal antibody (MoAb) AM34 (IgG1) which was prepared by a hybridoma constructed from fusion between murine myeloma cells and murine splenocytes. Crude amyloid proteins which were used as immunogen, were extracted from the kidney of a patient with rheumatoid arthritis by the distilled water method. This antibody strongly reacted with all 8 cases of secondary amyloidosis, but did not react or very weakly reacted with 17 tissue sections of primary or myeloma-associated amyloidosis. Other amyloid tissues did not give any positive reaction. Interestingly, 6 brain tissues of Alzheimer's disease clearly showed positive staining with this antibody, whereas two apparently normal brain tissues exhibited negative staining. Senile plaque cores, neurofibrillary tangles (weakly stained) and cerebrovascular amyloid in Alzheimer's disease were stained. Absorption of the MoAb AM34 with the crude amyloid proteins abolished the immunoreactivity of the MoAb AM34 not only with the kidney tissue section of the secondary amyloidosis, but also with the above mentioned portions of the brain in the case of Alzheimer's disease. Therefore, these immunohistological data suggest that the MoAb AM34 recognizes common epitope which exists in amyloid deposits of both secondary amyloidosis and Alzheimer's disease. An inhibition test on the kidney section showed that the reactivity of MoAb AM34 was not at all inhibited by the pretreatment of the section with 10 times higher concentration of anti-human amyloid A (AA) MoAb KM268 which was prepared against synthetic peptides of AA protein, suggesting that MoAb AM34 might react with amyloid-related protein other than AA protein. In addition, MoAb KM268 did not react with any lesions in Alzheimer's disease.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 3183130 | Quantification of cord deformation and dynamics during flexion and extension of the cervic | 1988 Nov | The magnetic resonance (MR) cine display of flexion and extension (F/E) manoeuvres in the cervical spine has proved useful in the evaluation of cord compression due to bone and joint instability, spondylosis, and multiple tumours. It has advantages over X-ray F/E and CT myelography in that it is noninvasive and produces images with high soft tissue contrast. The MR F/E technique does have its limitations, however, in that each structure in the images has a degree of independent movement and rotation that can make visual interpretation difficult. It also does not address the problem of assessing the relative significance of each lesion where numerous lesions may be present, for example, in compression due to spondylosis, rheumatoid arthritis, or neurofibromatosis. In this paper a novel technique is described that produces quantitative indices of cord deformation and dynamics during MR F/E. A computer program automatically calculates a series of contiguous profiles perpendicular to the cord throughout its length and for each image in the manoeuvre. Orthogonal polynomial curve fitting techniques are used to fit these profiles and extract statistical parameters that are quantitative indices of deformation and dynamics. The four main parameters calculated are kurtosis as an index of bilateral cord compression, skewness as an index of unilateral or asymmetric contact pressure, angulation as a measure of cord deformation about a lesion, and anteroposterior cord width as a direct measure of indentation and attenuation. Illustrative examples of results from normal volunteers and patients suffering from cervical myelopathy are presented. The technique may prove particularly useful to the spinal surgeon in assessing the relative significance of individual lesions and may also be a powerful research tool in the study of cord biomechanics in the living body. | |
| 2842744 | A comparison of the effect of timegadine, levamisole, and D-penicillamine on human neutrop | 1988 May | The effect of timegadine, a novel experimental antirheumatic drug, on human neutrophil (PMN) 5-lipoxygenase activity and leukotriene B4 (LTB4) chemotaxis was compared with that of two second-line antiinflammatory drugs, D-penicillamine and levamisole. 1-14C-Arachidonic acid (AA) was incorporated into the purified cells until steady state conditions were obtained. After preincubation with serial dilutions of the three drugs, AA release and metabolism was stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thin-layer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxis of PMNs towards LTB4 was measured in a modified Boyden chamber. Timegadine showed dose-dependent inhibition of both the 5-lipoxygenase pathway (IC50 3.4 x 10(-5) M), and of chemotaxis (IC50 3 x 10(-4) M). Inhibition of the release of AA from phospholipids, however, occurred only at therapeutically irrelevant doses (millimolar concentrations). Levamisole and D-penicillamine did not inhibit any of the cell functions investigated. Inhibition of both neutrophil motility and cellular synthesis of pro-inflammatory eicosanoids, may thus contribute to the clinical effects of timegadine in rheumatoid arthritis. | |
| 3143894 | Antigenic relatedness of a strongly immunogenic 65 kDA mycobacterial protein antigen with | 1988 Jan | In gene libraries of Mycobacterium bovis BCG, Mycobacterium tuberculosis and Mycobacterium leprae recombinants were frequently found expressing an immunodominant 65 kDa protein antigen. In this study polyclonal and monoclonal antibodies against the 65 kDa antigen were found to react with a variety of different bacteria. Furthermore it is shown that the 65 kDa mycobacterial protein belongs to the family of antigens previously designated 'common antigen' due to their presence in a large variety of bacterial species. The molecular weight of this common antigen in 17 bacterial species was determined and it varied from 59 to 65 kDa. These bacteria included Gram-negative, Gram-positive and archae-bacteria, indicating that this antigen consists of members of an evolutionary well-conserved protein family. The 65 kDa protein was located in the cytoplasmic fraction of both Escherichia coli K12 and M. bovis BCG. Its function for the bacterial cell is presently unknown. The immunological relatedness of this common antigen to the MbaA protein might indicate a role in the etiology of rheumatoid arthritis, as was recently suggested for the mycobacterial 65 kDa antigen. | |
| 3499170 | Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and it | 1987 Sep | Highly purified and cloned preparations of interleukin-1 (IL-1) were found to antagonize the capacity of erythropoietin (Epo) to stimulate the proliferation of mouse spleen and bone marrow erythroid precursor cells (EPC) in culture. Cloned murine IL-1 and purified and cloned human IL-1 alpha and IL-1 beta were approximately equipotent in this assay. IL-1 inhibited the proliferation response of EPC even when added as long as 17 h after Epo, suggesting that IL-1 does not affect binding of Epo to receptors or biochemical events following shortly thereafter. Indomethacin did not influence the inhibitory effect of IL-1 on Epo-induced proliferation, and PGE2 had no demonstrable effect on the process. Tumor-necrosis factor-alpha and interferons beta 1, and gamma did not affect Epo-induced proliferation. It is suggested that IL-1 mediated antagonism of the effects of Epo on erythroid precursors is a factor in the pathogenesis of many types of hypoplastic anaemia, including those associated with infections, rheumatoid arthritis and systemic lupus erythematosus, giant-cell arteritis, graft-versus-host disease and disorders associated with lymphocyte-mediated suppression of erythropoiesis. | |
| 3472244 | Presence of antibodies against a cell-surface protein, cross-reactive with DNA, in systemi | 1987 May | Antibodies against a cell-surface protein, cross-reactive with double-stranded DNA, were detected in the serum of 25 patients with active human systemic lupus erythematosus (SLE), defined on the basis of the revised American Rheumatism Association classification. Among these sera, two did not display anti-DNA antibodies, as shown by Farr assay, solid-phase radioimmunoassay, and Crithidia luciliae test. Five other SLE patients were consecutively studied in active and remission states. Antibodies against the protein were detected in the serum of the 5 SLE patients when they were in active phase but not in the serum of the same patients in inactive phase of the disease. The anti-protein antibodies were not found in the serum of 10 inactive SLE patients or in the sera of 10 normal human controls, 10 patients with rheumatoid arthritis, 5 patients with scleroderma, and 4 patients with primary sicca syndrome. Taken together, these results strongly suggest that antibodies against this cell-surface protein could provide a better diagnosis marker and activity index than anti-DNA antibodies in SLE. | |
| 2322285 | Tissue inhibitor of metalloproteases (TIMP) is matrix associated in aortic tissue: report | 1990 Mar 30 | Tissue inhibitor of metalloproteinases (TIMP) is the major inhibitor of collagenase, gelatinase, proteoglycanase, stromelysin, and metalloelastases. An imbalance between proteases and inhibitors has been implicated in numerous disease processes including tumor invasion, rheumatoid arthritis, emphysema, and aortic aneurysm disease. The purpose of this investigation was to develop a polyclonal antibody to recombinant TIMP and establish an immunoassay to measure immunoreactive protein in normal and diseased tissues. A polyclonal antibody was produced in rabbit against recombinant human TIMP which was characterized and used to establish a radioimmunoassay. The assay was used to measure immunoreactive protein in fibroblast conditioned medium, human serum, and aortic extracts. There was more immunoreactive TIMP in matrix associated urea extracts than soluble salt extracts from human aorta, suggesting that TIMP is matrix associated. The sensitivity of the assay enables the specific measurement of this inhibitor in serum, fibroblast culture medium, and tissue extracts. | |
| 3536423 | Oxaprozin. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and | 1986 Oct | Oxaprozin is a newer non-steroidal anti-inflammatory drug advocated for use in painful rheumatic and inflammatory conditions. As is the case with some other newer non-steroidal anti-inflammatory drugs, oxaprozin offers the convenience of once-daily administration. Published data suggest that oxaprozin 1200 mg once daily is comparable in effectiveness with usual dosages of aspirin, ibuprofen, indomethacin, naproxen, piroxicam and sulindac in the treatment of rheumatoid arthritis and osteoarthritis. More controlled clinical trials in adequate numbers of patients are necessary to evaluate its potential in other rheumatic and inflammatory conditions. Oxaprozin produced fewer gastrointestinal side effects than aspirin, and the short term tolerability of oxaprozin was similar to that of other non-steroidal anti-inflammatory drugs. If further definition of its efficacy and tolerability compared with other non-steroidal anti-inflammatory drugs during long term therapy confirms these initially favourable results, then oxaprozin would appear to offer a useful and convenient alternative in the treatment of painful rheumatic and inflammatory conditions. | |
| 3752071 | Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive | 1986 Sep | Although D-penicillamine has been used effectively in the management of a variety of diseases such as cystinuria, Wilson's disease, rheumatoid arthritis, and progressive systemic sclerosis, several toxic drug reactions have been observed with prolonged administration of this agent. One of the most serious side effects is the renal changes that occur following several months of use. We now report two patients with scleroderma who developed serologic evidence of lupus and crescentic glomerulonephritis during treatment with D-penicillamine. Both patients responded to pulse methylprednisolone and subsequent daily steroids. We also review the current information available on the variety of penicillamine nephropathies. | |
| 1959264 | Unicompartmental versus total knee arthroplasty in the same patient. A comparative study. | 1991 Dec | The purpose of this study was to compare unicompartmental knee arthroplasty (UKA) with total knee arthroplasty (TKA) and more specifically to evaluate the role of the patella in patient preference between UKA and TKA. A group of 23 patients were chosen, each with a UKA in one knee and a TKA in the opposite knee. As a subset of the group, 13 patients were compared who had not had patellar resurfacing on their TKA side (Group A) versus ten patients who had patellar resurfacing (Group B). Each patient had a UKA and TKA performed during the same hospitalization. Each patient's resurfacing was performed by the same surgical team. Moreover, inpatient care and physical therapy for each patient's respective UKA and TKA were the same. Patient evaluation consisted of chart review, joint registry data, and telephone interviews that focused on patient preference regarding pain, stability, "feel," and ability to climb stairs. The 23 patients studied had an average follow-up period of 81 months (range, 38-153 months). There were 14 men and ten women with an average age of 67 years. Preoperative diagnosis was osteoarthritis in 22 patients and rheumatoid arthritis in one patient. Range of motion (ROM) improved from a preoperative mean of 106 degrees to 123 degrees postoperatively on the UKA side. Mean ROM for the Group A TKAs improved from 104 degrees to 109 degrees, whereas the Group B TKAs remained unchanged at 113 degrees. For patients surveyed in Group A, 31% stated that their UKA knee was their better knee overall, 15% stated that their TKA knee was their better knee overall, and 54% could find no difference.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 1783573 | Diversity in HLA-DR4-related DR,DQ haplotypes in Australia, Oceania, and China. | 1991 Dec | The relative distributions of 12 HLA-DR4-related DRB1 alleles in indigenous populations of Australia, Melanesia, Micronesia, Polynesia, and northern and southern China have been determined by analysis of oligonucleotide hybridization patterns of 406 examples of HLA-DR4. DRB1*0405 and DRB1*0410 were common DR4 alleles in Australian aborigines and in Melanesians, while DRB1*0403 was the predominant DR4 allele in coastal Melanesians, Micronesians, and Polynesians; DRB1*0406 was confined to Chinese. A novel DR4 allele, found in 30% of DR4-positive Australian aborigines but exclusive to one aboriginal population, was a combination of DRB1*04 and 0803 nucleotide sequences and was carried on a haplotype with DR4-like DQ linkage arrangements. DQA1 and DQB1 typing generated 12 DR4-related haplotypes; the population distributions of these reflected the ancestral affinities of aborigines and Melanesians, the overlaying of coastal Melanesia with pre-Polynesian DR4 alleles and the colonization of Micronesia by an independent, non-Polynesian group. DR4-related autoimmune disorders such as rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus (IDDM) are virtually unknown in indigenous populations of Australia and Oceania and this study confirmed that high-risk RA determinants, Dw4 and Dw14, occurred rarely. However, the DQw8 allele, thought particularly to predispose to IDDM, was present in the majority of DR4-positive Polynesians and Micronesians. |