Richard Bucala

Bio: Richard Bucala is an academic researcher from Yale University. The author has contributed to research in topics: Macrophage migration inhibitory factor & Cytokine. The author has an hindex of 119, co-authored 595 publications receiving 54607 citations. Previous affiliations of Richard Bucala include École Polytechnique Fédérale de Lausanne & Rockefeller University.

Adoptive transfer of a novel MIF receptor (CD74+) expressing memory T cell subpopulation is sufficient to transfer inflammatory arthritis

Abstract: Rheumatoid arthritis (RA) is characterized by relapsing disease and progressive autoimmune joint destruction. The mechanism(s) for disease recurrence in previously affected joints is unknown. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. We report a novel subpopulation of T cells expressing the MIF receptor CD74, which previously has not been considered to be present in T lineage cells. CD74+ T cells comprise 1% of lymph node T cell and exhibit an effector memory phenotype (CD3 + CD74 + CD44 + , CD62L low ). Notably, whole genome expression profiling (RNAseq) of CD74+ T cells revealed reduced expression of the immune checkpoint Ctla4 (3.5-fold, p=0.009), and increased expression of Stat4 and Ptpn22 (1.4-fold, p=0.001 and 0.86-fold, p=0.045), three genes that regulate T cell activation and also are linked genetically to RA pathogenesis. In the collagen-induced arthritis (CIA) mouse model of RA, we observed a 2-fold (p=0.023) expansion of CD74+ T cells after disease induction when compared to Mif −/− mice, which show no expansion of CD74+ T cells and reduced disease severity (disease score: WT: 7.8; Mif −/− : 1.4, p>0.001). Notably, adoptive transfer of CD74+ T cells from mice with established CIA into naive mice recapitulated joint inflammation (disease score: 4.3, p=0.001). Disease was not detectable in naive mice that received CD74-T cells from CIA hosts. This study identifies a novel population of effector memory T cells that are capable of transferring autoimmune joint inflammation. We hypothesize that MIF responsive CD74+ effector memory T cells mediate recurrent joint inflammation and may be amenable to specific targeting by emerging MIF-directed therapies.

Abstract 042: Cd74-dysregulation of Macrophage-trophoblastic Interactions in the Preeclamptic Placenta

Abstract: Objectives: Preeclamptic pregnancies feature placental anomalies. Villous trophoblast differentiation during placental development is regulated by feto-placental macrophages and disturbance of this well-balanced regulation can lead to pathological pregnancies. We hypothesized that Cluster of differentiation 74 (CD74) dysregulation of placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. Methods and Results: We performed microarray analysis of placental tissue. CD74 was one of the most down-regulated (-2.5 fold) genes in placentas from preeclamptic women. We confirmed this finding in early onset ( Conclusions: We found that CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation led to altered macrophage activation towards a pro-inflammatory signature, a disturbed crosstalk with trophoblasts and an abnormal placental morphology.

MIF is a Common Genetic Determinant of COVID-19 Symptomatic Infection and Severity

Abstract: Abstract Background Genetic predisposition to COVID-19 may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. Aim To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. Methods This retrospective case control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the United States, Hungary, and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. Results In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls (11% vs. 19%, OR: 0.54 [0.41, 0.72], p < 0.0001). Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR: 2.87 [1.42, 5.78], p = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, p < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, p = 0.01) and maximum CRP (r = 0.16, p = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. Conclusions In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7 MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of host genetics in different stages of COVID-19 infection.

Intersecting roads to rheumatoid arthritis.

Abstract: Rheumatoid arthritis (RA) occurs worldwide and affects all ethnic groups, albeit with varying incidence and severity. Over the last decade, there have been remarkable advances in our understanding of the pathogenesis of rheumatoid inflammation and in the application of new therapies. Our knowledge of the molecular pathways leading to immune activation, chronic joint inflammation, and local tissue destruction continues to increase; yet, while we have come to recognize common genetic and immunologic factors that contribute to disease, no single factor appears causative, and a cure for RA is still beyond our reach. Nosology remains fundamental to the investigation of clinical autoimmunity. Current pathogenic models of RA emphasize the development of a systemic immunologic abnormality, which may be incipient or genetically predetermined, that drives a sustained and tissue-destructive synovial inflammatory response. It is hypothesized that autoimmune triggers lead to the selfperpetuating activation of several arms of the immune system, involving neutrophils, dendritic cells, monocyte/ macrophages, and B and T lymphocytes (1). As a consequence of rheumatoid joint inflammation, the synovium develops into granulation tissue known as pannus, and the fibroblast-like synovial lining cells acquire a continuously activated state, show enhanced proliferation, and secrete high levels of growth factors and matrix-degrading enzymes that promote cartilage and bone erosion. Such properties endure in synovial fibroblasts in vitro, suggesting that these cells are persistently altered in the rheumatoid joint (2). Rheumatoid synovial fibroblasts have been shown to proliferate in an anchorage-independent manner, escape contact inhibition, form microfoci, and invade cartilage implants when engrafted into immunodeficient mice (3). Precisely how synovial fibroblasts acquire this long-term activated state after their removal from the RA milieu is unknown, but it may be the result of a re-entrant pathway involving autocrine mediators and mutually reinforcing signal transduction pathways. There is evidence in rheumatoid synovial fibroblasts of sustained activation of protooncogene expression and of the functional inactivation of the tumor suppressor gene p53, which regulates cell cycle progression. Regardless of the precise effector pathways that contribute to this persistent phenotype, immune/inflammatory stimuli play a critical role in the initiation and the perpetuation of the invasive and pro-proliferative properties of rheumatoid synoviocytes (4). Investigations of arthritis pathogenesis in humans suffer from severe practical limitations; beyond the identification of susceptibility and disease-modifying genes, an examination of the interplay of the early pathogenic events that lead to the clinical expression of autoimmunity is extremely difficult. Accordingly, animal models of RA continue to hold center stage in formulating our pathologic conception of rheumatoid inflammation, and they have proved useful in delineating the molecular features that underlie both immune abnormalities and the specific effector mechanisms that produce joint destruction. Mouse models in particular, given the ease by which precise genetic deletions may be created and studied, have been especially informative in identifying or validating candidate disease-causative or disease-modifying factors (5). Among such studies, genetic definition of transcription activators (i.e. proteins that bind to DNA regulatory sequences to regulate gene induction) have been invaluable for understanding the mechanisms by which immune signals, for instance, those triggered by antigen receptors or cytokines, initiate the network of responses that characterize rheumatoid inflammation (6). Bioinformatics, which relies on computational assistance to analyze many thousands of gene expression Dr. Bucala’s work was supported by the NIH. Richard Bucala, MD, PhD: Yale University School of Medicine, New Haven, Connecticut. Address correspondence to Richard Bucala, MD, PhD, Department of Medicine, Section of Rheumatology, The Anlyan Center, Suite 525, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520. E-mail: Richard.Bucala@Yale.edu. Submitted for publication November 15, 2010; accepted in revised form December 28, 2010.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Multilineage Potential of Adult Human Mesenchymal Stem Cells

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。