Dr. Xiaoli Li & Dr. Julie Baskin's paper entitled "The Unique Cytoplasmic Domain of Human FcγRIIIA Regulates Receptor-Mediated Function", published in the Journal of Immunology has been selected as the Department's paper of the month for November 2012.

Li-XiaoliDr. Xiaoli Li obtained a diploma in Biochemistry and a Master’s in virology both from Wuhan University, China. In 1992 he obtained a Ph.D. in Immunology from UAB. After a postdoctoral fellowship at Cleveland Clinic Foundation and a year as Instructor at Rush Medical Center, he returned to UAB where he joined Dr. Kimberly’s group. He is currently Assistant Professor in the Division of Clinical Immunology and Rheumatology. 

Dr. Li's current work combines the use of functional genomic analysis and high content multi-chromatic flow cytometry analyses to understand the effects of natural gene polymorphisms of FcγR genes, their unique regulation, and the associated down-stream signaling events in SLE autoimmunity.

Baskin-JulieDr. Baskin received a B.S. in Zoology from the University of Massachusetts at Amherst in 1980, her M.S. in Biology from Georgetown University in 1982, and her Ph.D. in Cell and Molecular Biology from the University of Alabama at Birmingham in 1991.  She was awarded an Immunologic Diseases and Basic Immunology Training Grant fellowship and joined the laboratory of Dr. Ed Lamon where she investigated idiotypic network activation to the hapten 2, 4 dinitrophenyl (DNP) and antibody-induced inhibition of sarcoma growth using monoclonal antibodies specific for Moloney murine sarcoma/leukemia cell surface antigen.  More recently, Dr. Baskin worked in the laboratory of Dr. Robert Kimberly where she had been investigating the role of protein kinase C (PKC) phosphorylation of the alpha-chain cytoplasmic domains of gamma-chain associated Fc receptors.  Research interests include receptor-initiated cell signalling and the contribution of the α-chain cytoplasmic domain to downstream cellular responses.

Dr. Robert Kimberly's research group is interested in the role of genetic factors in the normal function of the immune system and in development of autoimmune and immune-mediated inflammatory diseases such as systemic lupus erythematosus and systemic vasculitis. Our approach has focused on receptors for immunoglobulin (Fc receptors) as a model system and has explored molecular mechanisms of receptor signaling and the molecular basis for receptor polymorphisms in humans. Allelic variations in receptor structure profoundly affect receptor function. Our group has been a leader in developing several national research consortia for the study of human diseases, and we have demonstrated that certain low-binding alleles are enriched in SLE patients. More active alleles are over-represented in patients with vasculitis and severe renal disease. 

J Immunol. 2012 Nov 1;189(9):4284-94. doi: 10.4049/jimmunol.1200704. Epub 2012 Sep 28.
The Unique Cytoplasmic Domain of Human FcRIIIA Regulates Receptor-Mediated Function.
Li X, Baskin JG, Mangan EK, Su K, Gibson AW, Ji C, Edberg JC, Kimberly RP.

Ligand specificity characterizes receptors for Abs and many other immune receptors, but the common use of the FcR γ-chain as their signaling subunit challenges the concept that these receptors are functionally distinct. We hypothesized that elements for specificity might be determined by the unique cytoplasmic domain (CY) sequences of the ligand-binding α-chains of γ-chain–associated receptors. Among Fcγ receptors, a protein kinase C (PKC) phosphorylation consensus motif [RSSTR], identified within the FcγRIIIa (CD16A) CY by in silico analysis, is specifically phosphorylated by PKCs, unlike other FcRs. Phosphorylated CD16A mediates a more robust calcium flux, tyrosine phosphorylation of Syk, and proinflammatory cytokine production, whereas nonphosphorylatable CD16A is more effective at activation of the Gab2/PI3K pathway, leading to enhanced degranulation. S100A4, a specific protein-binding partner for CD16A-CY newly identified by yeast two-hybrid analysis, inhibits phosphorylation of CD16A-CY by PKC in vitro, and reduction of S100A4 levels in vivo enhances receptor phosphorylation upon cross-linking. Taken together, PKC-mediated phosphorylation of CD16A modulates distinct signaling pathways engaged by the receptor. Calcium-activated binding of S100A4 to CD16A, promoted by the initial calcium flux, attenuates the phosphorylation of CY, and, acting as a molecular switch, may both serve as a negative feedback on cytokine production pathways during sustained receptor engagement and favor a shift to degranulation, consistent with the importance of granule release following conjugate formation between CD16A+ effector cells and target cells. This switch mechanism points to new therapeutic targets and provides a framework for understanding novel receptor polymorphisms.

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