Biomedical subjects

Robert Winchester

Publications and source records attributed to Robert Winchester.

8 recordsLinked to original sources

PubMed2006

Reshaping Cinderella's slipper: the shared epitope hypothesis.

This issue of Arthritis Research and Therapy contains a succinct and elegant paper by Michou and colleagues that advances our understanding of the genetic basis of rheumatoid arthritis (RA) by reclassifying the contribution of RA susceptibility alleles according to their structure. This line of research is potentially important in our conceptualization of the mechanism of disease in RA, in predicting disease course and severity, and as a model for further studies on this topic. The author's approach to reassessing the molecular structure of the shared epitope redirects attention to using the binding properties of the major histocompatibility complex molecules associated with susceptibility to search for the peptides driving the autoimmune process underlying rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed2005

An affinity/avidity model of peripheral T cell regulation.

We show in these studies that Qa-1-dependent CD8+ T cells are involved in the establishment and maintenance of peripheral self tolerance as well as facilitating affinity maturation of CD4+ T cells responding to foreign antigen. We provide experimental evidence that the strategy used by the Qa-1-dependent CD8+ T cells to accomplish both these tasks in vivo is to selectively downregulate T cell clones that respond to both self and foreign antigens with intermediate, not high or low, affinity/avidity. Thus, the immune system evolved to regulate peripheral immunity using a unified mechanism that efficiently and effectively permits the system to safeguard peripheral self tolerance yet promote the capacity to deal with foreign invaders.

Animals↗

PubMed2004

Mother-to-child transmission of HIV-1: strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms.

The transmission of HIV-1 from mother to child during pregnancy is unlike other types of HIV-1 transmission because the child shares major histocompatibility complex (MHC) genes with the mother during a time while the mother is induced to tolerate the paternally derived fetal MHC molecules, in part through natural killer (NK) recognition of MHC polymorphisms. The relevance of these immune mechanisms to HIV-1 transmission was assessed by determining the HLA-B alleles of mother and infant. Almost half (48%) of mothers who transmitted with low viral loads had HLA-B*1302, B*3501, B*3503, B*4402, or B*5001 alleles, compared with 8% of nontransmitting mothers (P=0.001). Conversely, 25% of mothers who did not transmit despite high viral loads had B*4901 and B*5301, vs. 5% of transmitting mothers (P=0.003), a pattern of allelic involvement distinct from that influencing HIV-1 infection outcome. The infant's HLA-B alleles did not appear associated with transmission risk. The HLA-B*4901 and B*5301 alleles that were protective in the mother both differed respectively from the otherwise identical susceptibility alleles, B*5001 and B*3501, by 5 amino acids encoding the ligand for the KIR3DL1 NK receptor. These results suggest that the probable molecular basis of the observed association involves definition of the maternal NK recognition repertoire by engagement of NK receptors with polymorphic ligands encoded by maternal HLA-B alleles, and that the placenta is the likely site of the effect that appears to protect against transmission of maternal HIV-1 through interrelating adaptive and innate immune recognition.

Adolescent↗

PubMed2004

Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens.

Psoriatic arthritis is an interesting MHC class I allele associated autoimmune disease where injury is likely mediated exclusively by T cells. We used TCR beta-chain nucleotide sequencing to gain insight into the adaptive immune events responsible for this injury and determine whether the numerous oligoclonal expansions of this disease represent extreme determinant spreading among driving clones that recognize autoantigen or were non-Ag-driven, inflammation-related expansions. Because methotrexate suppresses but does not eliminate this inflammation, we hypothesized that clones persisting during methotrexate treatment would likely drive the inflammation. Seventy-six percent of the T cell clones in active tissue were polyclonal and unexpanded, accounting for 31% of transcripts. They were decreased greatly by methotrexate. Strikingly, most expanded clones in the inflamed joint did not persist during methotrexate treatment, were found only in inflammatory sites, exhibited no structural homology to one another, and were either CD4 or CD8 in lineage, suggesting they were non-autoantigen-driven, inflammation-related expansions. Only 12% of the expanded clones could be grouped into clonal sets distinguished by structurally homologous CDR3 beta-chain amino acid motifs suggesting Ag drive. These were exclusively CD8 in lineage, persisted during methotrexate administration, and were present in both joint fluid and blood implying they were candidate driver clones that recognized an autoantigen. However, a major set of putative driver clones exhibited a previously described EBV-specific beta-chain motif, emphasizing that the dominant feature of the disease was activation of multiple clones apparently lacking specificity for an inciting autoantigen.

Amino Acid Sequence↗

PubMed2004

The genetics of autoimmune-mediated rheumatic diseases: clinical and biologic implications.

This article emphasizes the interpretation of the meaning and significance of the genetic aspects of susceptibility to certain autoimmune-mediated rheumatic diseases. The familial aggregation and identical twin concordance that provides the basis of considering these as genetic diseases are reviewed. Major histocompatibility complex (MHC) genes are taken as the primary examples of candidate genes that regulate the immune response; the potential function of these genes in predisposing to autoimmune diseases is analyzed. Autoimmune diseases are discussed as the consequence of the role of MHC molecules encoded by different alleles that exhibit distinct peptide-binding properties and select a self reactive T-cell repertoire. The low penetrance rates of autoimmune-mediated rheumatic disease is used as an argument that stochastic events in the generation and postthymic maturation of the somatically expressed T-cell repertoire account for the characteristically delayed onset of these diseases. The importance of self-reactivity in the physiologic immune response is used as an argument that the events that are responsible for the development of an autoimmune disease are an untoward exaggeration of normal immune responsiveness, but not a qualitatively distinct biologic event.

Autoimmunity↗

PubMed2004

Relationship of HLA-DQ8 and severity of celiac disease: comparison of New York and Parisian cohorts.

BACKGROUND & AIMS: Celiac disease is a polygenic disorder associated with HLA-DQ2 or HLA-DQ8, which are present in greater than 90% of patients. The disease is considered milder in the United States compared with Europe. We assessed whether differences in the frequency of HLA type may account for differences in severity of the disease by using cohorts of patients from New York and Paris. METHODS: HLA-DQ typing was performed on patients with celiac disease in New York and Paris. Clinical and pathologic data were compared between the New York and Parisian cohorts and also correlated with the different HLA types (HLA-DQ2, HLA-DQ2/-DQ8, HLA-DQ8). RESULTS: Among these patients, the disease was milder in the New York cohort compared with the Parisian cohort. There were fewer patients with a classical presentation (45% and 89%, respectively; P < 0.001) and less severe pathology (total villous atrophy, 64% and 89%, respectively; P < 0.05), and less marked intraepithelial lymphocytosis (intraepithelial leukocytes [IELs]/100 enterocytes, 48.1 and 82.5, respectively; P < 0.0001). HLA-DQ2 homozygotes were less prevalent in the New York cohort compared with the Parisian cohort (59% and 79%, respectively; P = 0.08). HLA-DQ8 alleles were more prevalent in the New York cohort compared with the Parisian cohort (41% and 21%, respectively; P = 0.026). There was, however, no difference in the clinical or pathologic parameters of severity when we compared the groups based on HLA type. CONCLUSIONS: HLA-DQ8 alleles were increased in the New York cohort of patients with celiac disease; however, this did not account for less severe manifestations of the disease.

Adult↗

PubMed2002

Association between maternal and infant class I and II HLA alleles and of their concordance with the risk of perinatal HIV type 1 transmission.

We aimed to investigate the influence of class I and class II HLA specificities and of the concordance between maternal and infant HLA on vertical HIV-1 transmission. HLA typing of samples from mothers and infants enrolled in the Ariel study, a perinatal HIV-1 transmission cohort including 203 mother-infant pairs, was performed by serological and molecular methods. HLA effects were evaluated alone and by multivariate modeling considering also other known predictors of perinatal HIV-1 transmission (maternal viral load, antiretroviral therapy, duration of rupture of membranes, and histological chorioamnionitis). Modest associations were seen with specific HLA markers (increased risk with infant B67 and B58 and maternal DR1; decreased risk with maternal B12), but these were not statistically significant after adjusting for multiple comparisons. Mother-infant concordance at any class I locus was a strong predictor of transmission (odds ratio [OR], 4.16; p = 0.028). Transmission was not associated with class II concordance. Class I HLA concordance retained its importance after adjusting for maternal viral load, antiretroviral therapy, duration of rupture of membranes or histological chorioamnionitis. In multivariate modeling, only class I concordance (OR, 3.59; p = 0.069) and chorioamnionitis (OR, 3.79; p = 0.030) were retained as independent predictors of transmission. HLA alleles, and in particular the class I concordance between maternal and neonatal HLA, may regulate the risk of perinatal HIV-1 transmission.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

The molecular pathophysiology of subacromial bursitis in rotator cuff disease.

Little information exists on the molecular and biochemical pathophysiology of subacromial bursitis and rotator cuff disease. We investigated the pattern of expression of cytokines (interleukin [IL]-1beta, IL-1, IL-6, tumor necrosis factor [TNF] alpha, small inducible cytokines), metalloproteases, and cyclooxygenases in the subacromial bursa in patients with rotator cuff disease. Subacromial bursa specimens were prepared for molecular and biochemical analysis in patients undergoing shoulder surgery following an institutional review board-approved protocol. Specimens were analyzed for the presence of cytokines, metalloproteases, and cyclooxygenases by use of microarray for gene expression and immunohistocytochemistry. Microarray analysis for gene expression and immunohistochemistry demonstrated that the expression of several cytokine genes (TNF, IL-1alpha, IL-1beta, and IL-6) was increased in patients with subacromial bursitis compared with control specimens. Furthermore, the expression of metalloproteases (MMP-1 and MMP-9) and cyclooxygenases (COX-1 and COX-2) in the bursitis group was found to be increased as compared with controls. Although further investigation is required, these studies suggest that inflammation of the subacromial bursa does occur in patients with rotator cuff disease. These findings support the role of anti-inflammatory agents in the treatment of subacromial impingement and emphasize the importance of subacromial bursectomy to reduce inflammation in rotator cuff disease.

Bursitis↗