Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Handunnetthi, Lahiru; Ramagopalan, Sreeram; Ebers, George C.; Knight, Julian C.

doi:10.1038/gene.2009.83

Cited by 123 publications

(115 citation statements)

References 194 publications

(181 reference statements)

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“…In mammals, mhc2 expression is regulated at the transcriptional level by the class II transactivator, which is recruited to the mhc2 promoter by proteins selectively bound to the X1, X2, and Y promoter sequences that are required for optimal constitutive and cytokine-induced expression in both humans and mice. 27 Analysis of the zebrafish mhc2dab proximal promoter revealed the presence of these conserved elements within a 4-kb fragment upstream of the transcriptional start site (data not shown). This 4-kb regulatory domain of the mhc2dab gene was cloned upstream of GFP-LT and flanked by Tol2 recombination sequences.…”

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confidence: 99%

Characterization of the mononuclear phagocyte system in zebrafish

Wittamer

Gutschow

Traver

2011

Blood

179

180

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The evolutionarily conserved immune system of the zebrafish (Danio rerio), in combination with its genetic tractability, position it as an excellent model system in which to elucidate the origin and function of vertebrate immune cells. We recently reported the existence of antigenpresenting mononuclear phagocytes in zebrafish, namely macrophages and dendritic cells (DCs), but have been impaired in further characterizing the biology of these cells by the lack of a specific transgenic reporter line. Using regulatory elements of a class II major histocompatibility gene, we generated a zebrafish reporter line expressing green fluorescent protein (GFP) in all APCs, macrophages, DCs, and B lymphocytes. Examination of mhc2dab:GFP; cd45:DsRed doubletransgenic animals demonstrated that kidney mhc2dab:GFP hi ; cd45:DsRed hi cells were exclusively mature monocytes/macrophages and DCs, as revealed by morphologic and molecular analyses. Mononuclear phagocytes were found in all hematolymphoid organs, but were most abundant in the intestine and spleen, where they up-regulate the expression of inflammatory cytokines upon bacterial challenge. Finally, mhc2dab:GFP and cd45:DsRed transgenes mark mutually exclusive cell subsets in the lymphoid fraction, enabling the delineation of the major hematopoietic lineages in the adult zebrafish. These findings suggest that mhc2dab:GFP and cd45:DsRed transgenic lines will be instrumental in elucidating the immune response in the zebrafish. (Blood. 2011;117(26):7126-7135) IntroductionIn recent years, the zebrafish (Danio rerio) has proven to be a unique vertebrate model for the study of hematopoiesis. 1 The use of the zebrafish to study the ontogeny of leukocyte subsets, 2 immune cell migration, 3,4 and host-pathogen interactions 5 has provided new insights into our understanding of innate immunity in the developing vertebrate embryo. A major focus of previous studies was on the neutrophil response, because several transgenic reporter lines have been generated that mark this granulocyte subset. Whereas neutrophils generally constitute the first line of defense against invading pathogens, the role of other immune cell subsets in the innate immune response has received less attention. In addition to neutrophils, macrophages are key in the response to pathogen challenge. In the zebrafish embryo, primitive macrophages have been demonstrated to be capable of clearing injected bacteria by phagocytosis. 6 However, the absence of markers specific to macrophages has limited the study of this myeloid cell subset in the zebrafish.The mononuclear phagocyte system (MPS) comprises monocytes, tissue macrophages, and dendritic cells (DCs), as well as their lineage-committed progenitors. 7 The primary function of mature MPS cells is the clearance of pathogens by phagocytosis. This activity is crucial during immune challenge to clear invasive pathogens. Mononuclear phagocytes also play an important role in the removal of apoptotic cell corpses, especially during embryonic development. In mice, embryonic macrop...

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confidence: 99%

Characterization of the mononuclear phagocyte system in zebrafish

Wittamer

Gutschow

Traver

2011

Blood

179

180

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“…MHC class II consists of three classes of HLA-II antigens: HLA-DP, -DQ and -DR presenting peptide antigens derived from extracellular proteins to CD4+ T helper cells to elicit an immune response. Because MHC class II expression is cell-type specific and mainly restricted to thymic epithelial cells and bone marrow-derived antigen presenting cells it is not expected to be a problem in many stem cell applications (Handunnetthi et al, 2010). Natural killer (NK) cells participate in the innate immune response as they are capable of killing tumor cells and virally-infected cells.…”

Section: Basic Principles Of Antigen Presentation the Adaptive Immunmentioning

confidence: 99%

Immunogenicity and Immune-Modulating Properties of Human Stem Cells

Nehlin¹,

Isa²,

Barington³

2011

Stem Cells in Clinic and Research

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“…Their promoter contains regulatory elements collectively called the "SXY module", to which various proteins bind, including regulatory factor X (RFX) and the class II transactivator (CIITA) (Handunnetthi et al, 2010). Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4 + T cell activation which, paradoxically, favors HIV replication.…”

Section: Dr1mentioning

confidence: 99%