The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients.

In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA-DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease.

Oligoclonality of human intestinal intraepithelial T cells.

T cells bearing the T cell receptor alpha/beta (TCR-alpha/beta) are the predominant lymphocyte population in the human intestinal epithelium. To examine if normal intestinal intraepithelial lymphocytes (IEL) have a TCR repertoire distinct from the TCR-alpha/beta repertoire in peripheral blood lymphocytes (PBL), comparative analysis of relative V beta gene usage in IEL and PBL was performed by quantitative polymerase chain reaction. In each of the six individuals examined, one to three V beta families made up more than 40% of the total V beta transcripts detected in the IEL, whereas there was a more even distribution of V beta gene usage in the paired PBL. The predominant V beta families, especially V beta 1, V beta 2, V beta 3, and V beta 6, were frequently shared among IEL of different individuals. PCR cloning and sequence analysis of the predominant V beta 6 family in two individuals revealed an identical V-D-J-C sequence in 13 of 21 clones obtained from one donor, and a different repeated sequence in 18 of 27 clones examined in the second donor. These data suggest that the V beta skewing in IEL is due to an oligoclonal T cell expansion and may reflect the response of the intestinal mucosal immune system to a restricted set of as yet undefined antigens present in the gut.

Polymorphism in a T-cell receptor variable gene is associated with susceptibility to a juvenile rheumatoid arthritis subset.

This report demonstrates a T-cell receptor (Tcr) restriction fragment length polymorphism, defined by a Tcrb-V6.1 gene probe and Bgl II restriction enzyme, to be absolutely correlated with allelic variation in the coding sequence of a Tcrb-V6.1 gene. A pair of non-conservative amino acid substitutions distinguish the Tcrb-V6.1 allelic variants. An association of this Tcrb-V6.1 gene allelic variant with one form of juvenile rheumatoid arthritis (JRA) was established in a cohort of 126 patients. The association was observed in patients possessing the HLA-DQA1*0101 gene. Among HLA-DQA*0101 individuals, 19 of 26 patients (73.1%) carried one particular Tcrb-V6.1 gene allele as opposed to 11 of 33 controls (33%; p less than 0.005). Haplotypes carrying this HLA gene have previously been shown to confer increased risk for progression of arthritis in JRA. This demonstration of a disease-associated Tcrb-V gene allelic variant has not, to our knowledge, been previously reported and supports the contribution of polymorphism in the Tcr variable region genomic repertoire to human autoimmune disease.

Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

HLA-DQA1*0101 haplotypes and disease outcome in early onset pauciarticular juvenile rheumatoid arthritis.

To further investigate a clinical impression that patients with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) who carry HLA-DQw1 have more severe arthritis, we subtyped HLA-DQw1 in American midwestern patients with EOPA-JRA. The HLA-DQA1*0101 subtype was present in 10 of 19 patients who developed persistent polyarticular erosive disease compared with 18 of 92 healthy controls (chi 2 = 9.13, p = 0.003, RR = 4.6), and occurred more frequently in this polyarticular group than in patients without polyarticular erosive disease (chi 2 = 4.11, p = 0.040, RR = 3.0). The presence of HLA-DQA1*0101 was significantly lower in patients with chronic iridocyclitis than in patients without chronic iridocyclitis (chi 2 = 7.07, p = 0.008, RR = 0.21). In HLA-DQA1*0101 positive patients, DNA sequences of the beta-1 domain of the HLA-DQ alpha and HLA-DQ beta genes (HLA-DQA1*0101, HLA-DQB1*0501 and HLA-DQB1*0503) were identical to those in controls. In this midwestern EOPA-JRA population, HLA-DQA1*0101 or genes in linkage disequilibrium with it, are associated with a cohort of patients with EOPA-JRA with distinct clinical characteristics.

A distinct HLA-DRw8 haplotype characterizes patients with juvenile rheumatoid arthritis.

We studied the first domain of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci of 67 HLA-DRw8-positive Caucasians including 43 with early-onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA, alternatively known as early-onset pauciarticular juvenile chronic arthritis). Serology, restriction fragment length polymorphism (RFLP), and polymerase chain reaction (PCR) oligotyping revealed that 62, including all the EOPA-JRA patients, carried the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype. Approximately one-fifth of the controls carried atypical HLA-DRB1, HLA-DQA1, and/or HLA-DQB1 loci on their HLA-DRw8 haplotype confirmed by family studies. DNA sequences of HLA-DRB1, DQA1, and DQB1 alleles in patients and controls were identical to those previously reported. Disease association studies in 113 EOPA-JRA patients and 207 controls unselected for HLA-DRw8 revealed that the HLA-DRB1*0801, DQA1*0401, DQB1*0402 genotype was associated with a higher relative risk (RR) for disease (RR = 12.8, chi 2 = 48.8, P less than 10(-4)) than was the serologically defined presence of HLA-DRw8 (RR = 8, chi 2 = 39, P less than 10(-4)). Further analysis suggested that the DQ genes on HLA-DRw8 haplotypes are as likely as the DR genes to contribute to the pathogenesis of EOPA-JRA. This study increases to five the number of HLA-DR/DQ haplotypes identified in HLA-DRw8 Caucasians.

Juvenile rheumatoid arthritis, human leukocyte antigen, and other immunoglobulin supergene family polymorphisms.

The following four points are discussed in this study: (1) Human leukocyte antigen (HLA) genes are associated with all groups of juvenile rheumatoid arthritis patients to varying degrees. (2) These HLA associations are similar to those of some adult inflammatory arthropathies (rheumatoid arthritis and ankylosing spondylitis), but distinct in others. (3) Predisposition commonly involves a contribution from both of a subject's HLA haplotypes. (4) Unusual immunogenetic aspects include a HLA-DP association, independent of linkage disequilibrium with other class II genes, and a HLA-associated mechanism increasing the relative proportion of girls in the involved sibships.

Temporal patterns of response to D-penicillamine, hydroxychloroquine, and placebo in juvenile rheumatoid arthritis patients.

We calculated the time required for therapeutic benefit to become apparent following initiation of treatment with D-penicillamine (DP), hydroxychloroquine (HCQ), or placebo (each administered concomitantly with a nonsteroidal antiinflammatory drug) using data from a double-blind, randomized 12-month trial in 162 patients with juvenile rheumatoid arthritis. Using previously published criteria to classify the outcome, we found that 60% of the HCQ group, 46% of the DP group, and 39% of the placebo group responded favorably after 12 months of therapy. Data from examinations between the initial and final assessments were used to determine when the response first occurred. Approximately 50% of all patients who showed improvement at 12 months had already done so by 2 months. After 6 months, 96% of the DP group, 88% of the HCQ group, and 85% of the placebo group responders had met the criteria for response. The average time until response was attained was 105 days for the DP group, 129 days for the HCQ group, and 140 days for the placebo group. Our results indicate that a favorable response to these slow-acting antirheumatic drugs is unlikely if improvement has not occurred within the first 6 months of therapy.

Bloom's syndrome. Clinical features and immunologic abnormalities of four patients.

Immune function was studied in four patients (two girls and two boys, aged 30 months to 24 years) with documented Bloom's syndrome. Three patients had a decreased serum concentration of at least one subclass of immunoglobulins. All had normal or elevated proportions of circulating B cells but two of them had a decreased proportion of CD4-positive helper-inducer T cells. We consistently found a severely impaired in vitro proliferative lymphocyte response to the plant lectin pokeweed mitogen (PWM). This could not be overcome by using suboptimal or supraoptimal doses of PWM, or by adding recombinant interleukin 2. In vitro PWM-induced IgM production was absent or low in two of the three patients studied and this low production could not be increased by addition of hydrocortisone. T lymphocytes responded normally to the plant lectins phytohemagglutinin and concanavalin A. T cells preactivated with phytohemagglutinin also normally proliferated in response to interleukin 2. It has previously been shown that lymphocyte activation with PWM involves both B and T cells and proceeds via an alternative pathway. The data thus indicate that patients with Bloom's syndrome have a specific defect in this PWM-induced alternative pathway of lymphocyte activation.

HLA and altered sex ratios in juvenile rheumatoid arthritis sibships.

Analysis of sex ratio in 301 siblings of 150 patients with early-onset pauciarticular juvenile rheumatoid arthritis revealed a male-to-female ratio of 1:2.00 in sibships with an HLA-B44+ proband, compared with a ratio of 1:1.05 in other sibships (G2 = 6.07, df = 1, p = 0.014). The siblings had a sex ratio of 1:0.8, when the HLA-B44 antigen was present in either parent but not transmitted to the proband. The capacity to distort the sex ratio was limited therefore to disease-associated HLA-B44 haplotypes.