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Matthew C Cook

Publications and source records attributed to Matthew C Cook.

10 recordsLinked to original sources
PubMed2006

ENU-mutagenesis: insight into immune function and pathology.

In random chemical mutagenesis, gene discovery is driven by phenotypes rather than by hypotheses. A standard dose of N-ethyl-N-nitrosourea results in approximately 30 coding mutations in male G1 mice, of which approximately 4 can be propagated to homozygosity in 3 generations. In recent years, large-scale screens of such G3 mice for phenotypes of interest to immunologists have revealed clues to the number of genes responsible for key immune responses, such as innate recognition of pathogens and autoantibody production. More than 20 of the phenotypes that exhibit a simple (Mendelian) pattern of inheritance have been mapped. Novel alleles have revealed new pathways of host defense, allergy and autoimmunity.

Alleles↗
PubMed2006

The influence of structural features on facile McLafferty-type, even-electron rearrangements in tandem mass spectra of carboxylate anions.

In contrast to the well-described McLafferty rearrangement in odd-electron cations, relatively little has been reported on comparable rearrangements in even-electron ions, especially negative ions. This work reports a systematic study using tandem mass spectrometry (MS/MS) fragment ion spectra of carboxylate anions having a suitably acidic proton in the gamma position. The rearrangement process was studied in both ion trap and triple quadrupole mass spectrometers; characteristic enolate anions and stable neutral products were formed at low collision energies. The process has diagnostic and analytical potential in, for example, the analysis of peptides having C-terminal serine residues and of 3-hydroxy- or 3-aminocarboxylic acids in complex mixtures.

Acrylates↗
PubMed2005

A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity.

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.

Amino Acid Sequence↗
PubMed2004

B cell biology, apoptosis, and autoantibodies to phospholipids.

Systemic autoimmune diseases are characterised by the development of a relatively narrow spectrum of autoantibodies. These are of considerable diagnostic value. In addition, in some diseases, including anti-phospholipid syndrome, these autoantibodies can be directly pathogenic. Understanding how these autoantibodies are formed represents an important avenue towards understanding the pathogenesis of systemic autoimmune disease itself. The minimum requirements for production of autoantibodies are self-reactive B cells and the availability of autoantigen. In other words, their formation is determined by factors that shape the B cell repertoire and the distribution and immunogenicity of the relevant autoantigens. On the B cell side, the propensity to produce autoantibodies depends on the fidelity of B cell self-tolerance mechanisms, B cell differentiation and selection into different peripheral compartments. These processes are interdependent, because both selection into different peripheral and mechanisms of B cell self-tolerance are influenced by signalling through the B cell receptor (BCR). On the antigen supply side, apoptotic cells appear to be a crucial source of antigenic targets of systemic autoimmunity, and elaborate mechanisms exist to ensure that apoptotic corpses undergo efficient disposal and do not become immunogenic. Several defects have been described where the disposal of apoptotic cells is compromised leading to their accumulation in parenchymal organs. These may become immunogenic resulting in autoantibody formation. The mechanisms that lead to progression from accumulation of autoantigen, in the form of apoptotic corpses, to the production of autoantibodies by self-reactive B cells within different parts of the peripheral repertoire are discussed.

Animals↗
PubMed2003

Recirculating and germinal center B cells differentiate into cells responsive to polysaccharide antigens.

Antibodies against bacterial capsular polysaccharides play a critical protective role. Responses to these antigens can occur without the help or control of T cells and are associated with marginal zone (MZ) B cells. Capsular antigens are diverse and some cross-react with self-carbohydrate epitopes. This diversity may explain the recruitment of non-autoreactive recirculating B cells and memory B cells to the MZ in addition to other B cells, some of which are weakly autoreactive cells, that are recruited to the MZ without entering the recirculating pool. To test whether memory B cells respond to polysaccharide-based antigens, mice with hapten-specific memory B cells were challenged with hapten-polysaccharide. Hapten-specific plasma cells producing high affinity antibody with Ig V-region mutations were induced. To test whether naive recirculating B cells can form MZ cells that respond to polysaccharide, recirculating B cells from lymph nodes were transferred into Rag-1-deficient mice. MZ cells differentiated from the donor cells without proliferation or T cell help and responded to polysaccharide-based antigen. The differentiation of B cells both from germinal centers and the recirculating pool to the MZ phenotype is likely to make an important contribution to the repertoire of B cells that respond to polysaccharide antigens.

Animals↗
PubMed2003

Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis.

In a genome-wide ENU mouse mutagenesis screen a recessive mouse mutation, unmodulated, was isolated with profound defects in humoral immune responses, selective deficits in B cell activation by antigen receptors and T cell costimulation by CD28, and gradual development of atopic dermatitis with hyper-IgE. Mutant B cells are specifically defective in forming connections between antigen receptors and two key signaling pathways for immunogenic responses, NF-kappaB and JNK, but signal normally to calcium, NFAT, and ERK. The mutation alters a conserved leucine in the coiled-coil domain of CARMA-1/CARD11, a member of the MAGUK protein family implicated in organizing multimolecular signaling complexes. These results define Carma-1 as a key regulator of the plasticity in antigen receptor signaling that underpins opposing mechanisms of immunity and tolerance.

Aging↗
PubMed2003

Extrafollicular antibody responses.

In adaptive antibody responses, B cells are induced to grow either in follicles where they form germinal centers or in extrafollicular foci as plasmablasts. Extrafollicular growth typically occurs in the medullary cords of lymph nodes and in foci in the red pulp of the spleen. It is not a feature of secondary lymphoid tissue associated with the internal epithelia of the body. All types of naïve and memory B cells can be recruited into extrafollicular responses. These responses are associated with immunoglobulin class switching but, at the most, only low-level hypermutation.

Animals↗
PubMed2002

Analysis of B cell memory formation using DNA microarrays.

DNA microarray analysis of B cell subsets has identified comprehensive programs of gene expression that distinguish B cells at discrete stages of differentiation. The next task is to identify key genetic signals within these complex programs that regulate the dynamic cellular events during B cell activation in vivo. After stimulation with antigen, naïve B cells proliferate and differentiate, and then produce antibodies. Crucial qualitative differences in antibody responses are observed depending on whether or not B cells receive T cell help during activation. Proteins, lipopolysaccharides, and polysaccharides stimulate T-dependent (TD), T-independent type 1 (TI-1), and type 2 (TI-2) antibody responses, respectively. Only TD responses generate somatically mutated antibody-forming (plasma) cells and memory B cells, which produce high affinity anamnestic responses to subsequent antigen challenge. Somatic mutation of immunoglobulin genes occurs during B cell proliferation in germinal centres (GC), which are typical in TD responses but rare in TI responses. However, we have described a model, which is exceptional because numerous large GC form in response to a model TI-2 antigen, (4-hydoxy-3-nitrophenyl) acetyl (NP)-Ficoll. Significantly, these GC undergo involution before memory B cells are generated. This model provides an opportunity to investigate the genetic signals that drive memory cell formation, and we have compared global gene expression in TI and TD GC to identify a relatively small number of genes that are differentially expressed between the two prototypic B cell responses. This model demonstrates how genome-scale technology can be adapted to investigate specific aspects of B cell biology.

Animals↗