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Rheumatoid arthritis (RA) usually improves during pregnancy and recurs postpartum. Fetal cells and cell‐free DNA reach the maternal circulation during normal pregnancy. The present study investigated dynamic changes in levels of fetal DNA in serum from women with RA and inflammatory arthritis during and after pregnancy to test the hypothesis that the levels of circulating fetal DNA correlate with arthritis improvement.Twenty‐five pregnant patients were prospectively studied. A real‐time quantitative polymerase chain reaction panel targeting unshared, paternally transmitted HLA sequences, a Y chromosome–specific sequence, or an insertion sequence within the glutathione S‐transferase M1 gene was used to measure cell‐free fetal DNA. Results were expressed as fetal genomic equivalents per milliliter (gE/ml) of maternal serum. Physical examinations were conducted during and after pregnancy.Levels of fetal DNA in women with improvement in or remission of arthritis were higher than those in women with active disease, especially in the third trimester. Overall, an inverse relationship between serum fetal DNA levels and disease activity was observed (P < 0.001). Serum fetal DNA increased with advancing gestation, reaching median levels of 24 gE/ml (range 0–334), 61 gE/ml (range 0–689), and 199 gE/ml (range 0–2,576) in the first, second, and third trimesters, respectively, with fetal DNA clearance observed postpartum. Arthritis improvement was initially noted in the first trimester for most patients, increased further or was sustained with advancing gestation, and was active postpartum.Changes in serum fetal DNA levels correlated with arthritis improvement during pregnancy and recurrence postpartum. Immunologic mechanisms by which pregnancy might modulate RA activity are described. [ABSTRACT FROM AUTHOR]

Maternal–fetal cell transfer during pregnancy can lead to long‐lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother–son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women.HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers.Sons with SLE were HLA‐identical with their mothers (bidirectionally compatible) for the basic HLA–DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio [OR] 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE‐associated HLA genes (encoding HLA–DR2 or HLA–DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus.We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation. [ABSTRACT FROM AUTHOR]

Microchimerism (Mc), originating from bidirectional fetal–maternal cell traffic during pregnancy, has recently been identified in healthy adults and in patients with scleroderma (systemic sclerosis [SSc]). This study was undertaken to investigate the frequency and quantitative levels of maternal Mc (MMc) in healthy women and women with SSc. HLA-specific primers and fluorogenic probes were used in real-time quantitative polymerase chain reaction assays to detect and quantify MMc by targeting noninherited, nonshared HLA sequences. DNA-based HLA typing was conducted in 67 proband-mother pairs and in all children if the proband was parous. Statistical analysis was limited to 50 proband-mother pairs (including 32 healthy women and 18 women with SSc) in whom MMc could be distinguished from potential fetal Mc. MMc in peripheral blood mononuclear cells was more frequent among women with SSc (72%) than healthy women (22%) (odds ratio 9.3, P = 0.001). However, levels of MMc, expressed as the genome equivalent of maternal cells per million (gEq/mil), were not significantly different (0–68.6 gEq/mil in SSc patients, 0–54.5 in healthy women). In additional studies, positivity for MMc was demonstrated in a bone marrow aspirate from an SSc patient in whom peripheral blood had been found to be negative for MMc on 4 occasions, and tissue from a subsequent autopsy of this patient had MMc levels of 757 and 1,489 gEq/mil in the lung and heart, respectively. MMc is not uncommon in the peripheral blood of healthy adults, is increased in frequency in patients with SSc, and may be present in bone marrow and disease-affected tissues although absent in the peripheral blood. [ABSTRACT FROM AUTHOR]

A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings. We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL. Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P = 0.001]) and 10q21 (D10S1221 [P = 0.0002] and D10S1225 [P = 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 × 10-12). Inclusion of DRB1∗04 as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1∗04 or rheumatoid factor positivity as covariates. These results provide a rational basis for pursuing high-density linkage and association studies of RA in several regions outside of the HLA region, particularly on chromosomes 1p, 1q, and 18q. [ABSTRACT FROM AUTHOR]