Dr. Winchester has had a sustained interest in autoimmunity and autoimmune diseases. His laboratory is focused on understanding the genetic basis of susceptibility to autoimmune disease and the mechanisms responsible for triggering and mediating autoimmune injury. His earlier studies defined the molecular importance of IgG rheumatoid factors in rheumatoid arthritis and other autoantibodies in various human autoimmune diseases. He also introduced the use of F(ab')2fragments into cell surface immunofluorescence. Moreover, Dr. Winchester was one of the first to identify human MHC class II molecules on B cells and monocytes and the first to show that they were expressed on human T cells as markers of activation.
As importantly, his studies of the polymorphisms of MHC molecules have provided the basis of establishing the link between MHC genotype and susceptibility to multiple forms of autoimmunity. For example in the late 1980's Dr. Winchester and colleagues showed that susceptibility to rheumatoid arthritis was determined by sequences in the HLA-DR beta chain of MHC class II molecules, and formulated the shared MHC 'epitope' hypothesis. This hypothesis provides a molecular basis for susceptibility to rheumatoid arthritis,implicating a region on the MHC molecule that both binds a peptide side chain and interacts with the TCR. This key discovery has emphasized the importance of the modern means of HLA typing, which involves DNA sequencing of the MHC genes and the theoretical basis for the discovery of antigens that initiate autoimmune disease.
More recently, Dr. Winchester has coupled the DNA sequencing of the MHC genes with the analysis and high throughput DNA sequencing of human T cell receptor genes to permit molecular analysis of the cognitive T cell/peptide/MHC recognition events that underlie the role of the adaptive immune system in autoimmunity.
His laboratory is also interested in the role played in immunity and by the triggering of innate immune receptors present on CD8 T cells, that is relevant to entities as diverse as celiac disease, psoriatic arthritis and the maternal-infant transmission of HIV-1.
During the last several years Dr. Winchester’s laboratory has joined forces with several other laboratories to advance understanding of problems in human autoimmune disease. One group of collaborative interactions is with the Dr. Chess and his colleagues within the Autoimmunity Center of Excellence. Another is with Dr. Bana Jabri on problems of celiac disease. A major collaboration exists with Prof. Oliver FitzGerald of Dublin using a large Irish cohort to study the genetic susceptibility and T cell repertoire in psoriatic arthritis.
Dr. Winchester’s laboratory has had a longstanding interest in the molecular basis of the synovial lining hyperplasia that occurs in certain forms of arthitis and mediates cartilage and joint erosion. His laboratory did much to characterize the distinctive phenotype of cultured rheumatoid arthritis synoviocytes. His identification of a number of genes, including SDF-1 and SLIT-3 in these synoviocytes suggested that some synoviocytes, particularly those exhibiting a “dentritic” or “stellate” morphologys resembled the mesenchymal stem cells of bone marrow, and that the inappropriate expression of some of these transcripts was responsible for cartilage invasion. Currently microarray analysis and real-time PCR is being used to extend insight into the developmental stage of these synoviocytes using cloned cells.
1. Jabri, B., Selby, J.M., Negulescu, H., Lee, L., Roberts, A.I., Beavis, A., Lopez-Botet, M., Ebert, E.C., and Winchester, R.J. (2002) TCR Specificity Dictates CD94/NKG2A Expression by Human CTL Immunity
2. Robert Winchester, Jane Pitt, Manhattan Charurat, Laurence S. Magder, Harald H. H. Goring, Alan Landay, Jennifer S. Read, William Shearer, Edward Handelsman, Katherine Luzuriaga, George V. Hillyer, William Blattner (2004) Mother-to-Child Transmission of HIV-1: Strong Association with Certain Maternal HLA-B Alleles Independent of Viral Load Implicates Innate Immune Mechanisms The Journal of Acquired Immune Deficiency Syndromes
3. Winchester, R., Y. Chen, S. Rose, J. Selby, and W. Borkowsky (1995) MHC class II DR alleles DRB1*1501 and those encoding HLA-DR13 are preferentially associated with a diminution in maternally transmitted HIV-1 infection in different ethnic groups: determination by an automated sequence-based typing method Proc. Natl. Acad. Sci. USA.
4. Itescu, S., S. Rose, E. Dwyer, and R. Winchester (1995) Grouping HLA-B locus serologic specificities according to shared structural motifs suggest that different peptide-anchoring pockets may have contrasting influences on the course of HIV-1 infection Hum. Immunol.
5. Itescu, S., S. Rose, E. Dwyer, and R. Winchester. (1994) Certain HLA-DR5 and -DR6 major histocompatibility complex class II alleles are associated with a CD8 lymphocytic host response to human immunodeficiency virus type 1 characterized by low lymphocyte viral strain heterogeneity and slow disease progression Proc. Natl. Acad. Sci. USA
6. Itescu, S., J. Dalton, H. Zhang, and R. Winchester (1993) Tissue infiltration in a CD8 lymphocytosis syndrome associated with human immunodeficiency virus-1 infection has the phenotypic appearence of an antigenically driven response J. Clin. Invest.