Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
16
3
1996
Genes Responsible for Quantitative Regulation of Antibody Production
223-250
10.1615/CritRevImmunol.v16.i3.10
Anne
Puel
Laboratoire d'lmmunogenetique, Unite INSERM 255, Institut Curie, 26, rue d'Ulm, 75231 PARIS CEDEX 05, FRANCE
Denise
Mouton
Laboratoire d'lmmunogenetique, Unite INSERM 255, Institut Curie, 26, rue d'Ulm, 75231 PARIS CEDEX 05, FRANCE
antibody production
multigenic control
QTL mapping.
Evidence is first presented demonstrating that the individual capacity for antibody responsiveness has an inheritable component. The main evidence consists of spontaneous mutations causing either immunodeficiency or predisposition to autoimmunity in human and animals, and the involvement of some obvious candidate genes (in particular those belonging to the highly polymorphic histocompatibility and Igh loci), extensively analyzed in many mouse strain combinations. One finding constantly emerging from these studies is that single gene expression depends on environmental effects, lowering the genotype/phenotype correlation, but also on multigenic interactions appearing as background effects. The models available for the analysis of this multigenic regulation are discussed with special emphasis on the high and low antibody responder mice produced for this purpose by bidirectional selective breeding. The major advantage of this model is that the interline difference is huge and multispecifically expressed. The second part of the review presents the recent results on positional mapping of genes with immunomodulatory effects in this model and in one appropriate recombinant congenic strain series. This in vivo genetic dissection of antibody responsiveness discriminated the involvement of candidate genes and suggested that unsuspected genes might be identified by means of this wide open search.
Structural Aspects of Signal Transduction in B-Cells
251-274
10.1615/CritRevImmunol.v16.i3.20
Mauno
Vihinen
Department of Biosciences, Division of Biochemistry, P.O. Box 56, FIN-00014 University of Helsinki, Finland
C. I. Edward
Smith
Center for BioTechnology, Karolinska Institute, Department of Bioscience at NOVUM. S-14157 Huddinge, Sweden, and Department of Clinical Immunology, Karolinska Institute at Huddinge Hospital, S-14186 Huddinge, Sweden
signal transduction
Btk
XLA
protein kinases
SH2
SH3
PH
TH.
Signal transduction in hematopoietic cells is a highly specific process. The stimulation of B cell receptor following antigen binding triggers, as a first step, phosphorylation of the cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). Src family tyrosine kinases Blk, Fyn, Lck, and Lyn as well as spleen kinase, Syk, are activated to transmit the signal further. In this review the signaling events are discussed in structural terms. The factors related to B cell maturation and their targeted mutations are reviewed. During the last 2 years plenty of structural information concerning signaling molecules in B cells has been obtained by using X-ray crystallography, NMR spectroscopy, molecular modeling, and mutational analysis. The molecules discussed include Src family kinases, Syk, Grb2 adaptor protein, and Tec family kinases Bmx and Btk. The structure, function, and interactions of these signaling compounds are described in atomic detail.
Regulation of Immune Responses of the Intestinal Mucosa
277-309
10.1615/CritRevImmunol.v16.i3.30
Maria T.
Abreu-Martin
Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048
Stephan R.
Targan
Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048
intraepithelial lymphocytes
lamina propria lymphocytes
mucosal homing
antigen presentation
nonclassical MHC molecules
animal models of colitis.
The largest lymphoid organ in the body, the intestine, is also the most intriguing and complex. At its root, the gastrointestinal immune system must permit the absorption of nutrients while protecting against invasion of pathogens. In the process, it must sort through vast antigenic challenges and orchestrate an immune response appropriate to the occasion. Whereas the general outline of mucosal immunity has been defined with respect to the phenotype of the immune cells that compose the mucosal immune system, the ontogeny of these immune cells, and the regulation of IgA responses, the details that control mucosal T cell activation and suppression that coordinate this elaborate mucosal network continue to perplex. This review highlights unique aspects of T cell regulation within the intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) compartments when conpared with lymphocytes in the periphery. In general, IEL are largely extrathymically derived, have a limited TCR repertoire capable of recognizing common microbiologic Ags, and demonstrate predominantly cytolytic functions. LPL are thymically derived, highly activated lymphocytes with predominantly Th2 phenotype. LPL activation is distinct from classic memory T cells in their CD2/CD28 predominance that likely contributes to limiting TCR/CD3-mediated signals in the mucosa. Ag presentation in the gut may involve nonclassical, nonpolymorphic class I-like molecules expressed by epithelial cells that may positively select extrathymically derived lymphocyte populations as well as tolerize self-reactive lymphocytes. These special features of the mucosal immune system are integrated to downregulate immune responses to ubiquitous lumenal Ags.
Regulation of Class II MHC Expression
311-330
10.1615/CritRevImmunol.v16.i3.40
Wolfgang M.
Rohn
Departments of Physiology and Biophysics University of Alabama at Birmingham, Birmingham, AL 35294-0005
Yi-Ju
Lee
Departments of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005
Etty N
Benveniste
Departments of Physiology and Biophysics and Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005
antigen presentation
cytokines
CIITA
autoimmunity
signal transduction
transcription factors.
The class II genes of the major histocompatibility complex (MHC) encode the α/β heterodimeric glycoproteins that play a critical role in the induction of immune responses through presentation of processed antigen to CD4+ T lymphocytes. The constitutive expression of class II MHC antigens is restricted primarily to B cells, dendritic cells, thymic epithelium, and macrophages, although a wide variety of other cell types can be induced to express class II antigens after exposure to cytokines. The appropriate constitutive and inducible expression of class II MHC antigens is essential for normal immune function; thus, it is not surprising that aberrant expression on cell types normally class II MHC negative has been correlated with various autoimmune disorders, and lack of expression results in a severe combined immunodeficiency disorder called bare lymphocyte syndrome (BLS). In this review, we discuss the agents that both induce and inhibit class II MHC expression, the function of class II MHC antigens with an emphasis on the ability of these proteins to act as signal transducing molecules, and the molecular regulation of class II MHC expression.