Nancy Hogg | |
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| Known for | Study of Leukocyte Integrins |
| Scientific career | |
| Fields | Immunology |
Nancy Hogg FMedSci is an immunologist who has made major contributions in the field of adhesion molecules, focusing on the integrins expressed by leukocytes. [1] Hogg was elected to the Academy of Medical Sciences in 2002 and currently holds an emeritus position at the Francis Crick Institute, London.
Nancy Hogg studied for a BSc at the University of Toronto. She was awarded a PhD working with Rodney Porter firstly at the University of London and then at Department of Biochemistry, University of Oxford. This was followed by a post–doctoral period at National Institute for Medical Research and finally a position at the Imperial Cancer Research Fund (which became Cancer Research UK London Research Institute and is now part of the Francis Crick Institute). Hogg was located initially at University College London followed by a move to the main laboratories in Lincoln’s Inn Fields where she set up her laboratory focusing initially on the function of macrophages, but then increasingly on the adhesion molecules termed integrins expressed by all leukocytes.
Nancy Hogg’s PhD project involved the protein sequencing of immunoglobulin heavy chains identifying for the first time the heterogeneity that accounts for immunoglobulin specificity. [2] During a postdoctoral period at the Imperial Cancer Research Fund she co-discovered the protein that is now known as fibronectin. [3] Through study of leukocyte integrin LFA-1 and particularly special mAb 24, Hogg was the first to document that the state of integrin activity could be controlled by bound divalent cations. [4] [5] The active forms are linked to different cytoskeletal proteins, namely talin for high affinity and a-actinin for clustered intermediate affinity LFA-1 . [6] [7] The lab showed that the LFA-1 ligand ICAM-1 was a target for pathogen binding, for example the malaria parasite Plasmodium falciparum . [8] The generation of LFA-1 null mice revealed the central role of LFA-1 in leukocyte migration within lymph nodes in vivo. [9] [10] Hogg also first identified and characterised unique Leukocyte Adhesion Deficiency-III patients that expressed inactive leukocyte integrins. [11] This integrin malfunction was due to mutation in protein kindlin-3. [12]
Hogg has also studied the S100A8/S100A9 proteins that constitute 45% of neutrophil cytosolic protein. [13] [14] S100a9 null mice demonstrated that myeloid cells could function relatively normally without these proteins but they had a major role in responding to infections such as Streptococcus pneumoniae in terms of cytokine generation. [15]
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.
Leukocyte adhesion deficiency (LAD) is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a Glanzmann thrombasthenia-like bleeding tendency.
ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.
Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the VCAM1 gene. VCAM-1 functions as a cell adhesion molecule.
CD11c, also known as Integrin, alpha X (ITGAX), is a gene that encodes for CD11c.
Integrin, alpha L , also known as ITGAL, is a protein that in humans is encoded by the ITGAL gene. CD11a functions in the immune system. It is involved in cellular adhesion and costimulatory signaling. It is the target of the drug efalizumab.
Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.
Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene. The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1, L-selectin, and VLA-4 on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1.
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes. Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. LFA-1 belongs to the integrin superfamily of adhesion molecules.
In molecular biology, CD18 is an integrin beta chain protein that is encoded by the ITGB2 gene in humans. Upon binding with one of a number of alpha chains, CD18 is capable of forming multiple heterodimers, which play significant roles in cellular adhesion and cell surface signaling, as well as important roles in immune responses. CD18 also exists in soluble, ligand binding forms. Deficiencies in CD18 expression can lead to adhesion defects in circulating white blood cells in humans, reducing the immune system's ability to fight off foreign invaders.
Lymphocyte homing receptors are cell adhesion molecules expressed on lymphocyte cell membranes that recognize addressins on target tissues. Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs. These diverse tissue-specific adhesion molecules on lymphocytes and on endothelial cells contribute to the development of specialized immune responses.
Macrophage-1 antigen is a complement receptor ("CR3") consisting of CD11b and CD18.
Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.
Intercellular adhesion molecule 3 (ICAM3) also known as CD50, is a protein that in humans is encoded by the ICAM3 gene. The protein is constitutively expressed on the surface of leukocytes, which are also called white blood cells and are part of the immune system. ICAM3 mediates adhesion between cells by binding to specific integrin receptors. It plays an important role in the immune cell response through its facilitation of interactions between T cells and dendritic cells, which allows for T cell activation. ICAM3 also mediates the clearance of cells undergoing apoptosis by attracting and binding macrophages, a type of cell that breaks down infected or dying cells through a process known as phagocytosis, to apoptotic cells.
Intercellular adhesion molecule 2 (ICAM2), also known as CD102, is a human gene, and the protein resulting from it.
S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.
Integrin beta-7 is an integrin protein that in humans is encoded by the ITGB7 gene. It can pair with ITGA4 (CD49d) to form the heterodimeric integrin receptor α4β7, or with ITGAE (CD103) to form αEβ7.
Fermitin family homolog 3) (FERMT3), also known as kindlin-3 (KIND3), MIG2-like protein (MIG2B), or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene. The kindlin family of proteins, member of the B4.1 superfamily, comprises three conserved protein homologues, kindlin 1, 2, and 3. They each contain a bipartite FERM domain comprising four subdomains F0, F1, F2, and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome, leukocyte adhesion deficiency, cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore, they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis
A junctional adhesion molecule (JAM) is a protein that is a member of the immunoglobulin superfamily, and is expressed in a variety of different tissues, such as leukocytes, platelets, and epithelial and endothelial cells. They have been shown to regulate signal complex assembly on both their cytoplasmic and extracellular domains through interaction with scaffolding that contains a PDZ domain and adjacent cell's receptors, respectively. JAMs adhere to adjacent cells through interactions with integrins LFA-1 and Mac-1, which are contained in leukocyte β2 and α4β1, which is contained in β1. JAMs have many influences on leukocyte-endothelial cell interactions, which are primarily moderated by the integrins discussed above. They interact in their cytoplasmic domain with scaffold proteins that contain a PDZ domain, which are common protein interaction modules that target short amino acid sequences at the C-terminus of proteins, to form tight junctions in both epithelial and endothelial cells as polarity is gained in the cell.
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