Hydrolysis of inositol phospholipids by phospholipase C is initiated by either receptor stimulation or opening of Ca2+ channels. This was once thought to be the sole mechanism to produce the diacylglycerol that links extracellular signals to intracellular events through activation of protein kinase C. It is becoming clear that agonist-induced hydrolysis of other membrane phospholipids, particularly choline phospholipids, by phospholipase D and phospholipase A2 may also take part in cell signaling. The products of hydrolysis of these phospholipids may enhance and prolong the activation of protein kinase C. Such prolonged activation of protein kinase C is essential for long-term cellular responses such as cell proliferation and differentiation.

https://science.sciencemag.org/content/sci/258/5082/607.full.pdf

Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C

Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells

A method and apparatus for preparation of a substrate containing a plurality of sequences. Photoremovable groups are attached to a surface of a substrate. Selected regions of the substrate are exposed to light so as to activate the selected areas. A monomer, also containing a photoremovable group, is provided to the substrate to bind at the selected areas. The process is repeated using a variety of monomers such as amino acids until sequences of a desired length are obtained. Detection methods and apparatus are also disclosed.

Very large scale immobilized polymer synthesis

The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.

Cell biology of antigen processing in vitro and in vivo

Polymyositis and dermatomyositis belong to the group of inflammatory muscle diseases. This chapter deals only with the “idiopathic” polymyositis and dermatomyositis syndromes; parasitic, bacterial, spirochetal, and viral infectious myopathies will not be discussed. For recent reviews of the general subject, the reader may wish to refer to Banker and Engel (1986), Dalakas (1991, 1992), Engel (1992)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(03)14368-1.pdf

Polymyositis and Dermatomyositis

Cytolytic and membrane-perturbing properties of lysophosphatidylcholine.

T cell immune responses to haptens. Structural models for allergic and autoimmune reactions

Although hapten immune responses have been intensively studied in the mouse, very little is known about hapten determinants involved in human allergic reactions. Penicillins, as chemically reactive compounds of low molecular weight, constitute typical examples of hapten allergens for humans. Penicillins become immunogenic only after covalent binding to carrier proteins and in this form frequently induced IgE-mediated allergic reactions in patients subjected to antibiotic treatment. However, our previous data strongly indicated that penicillins also form part of the epitopes contacting the antigen receptors of beta lactam-specific T cells in allergic individuals. We have therefore investigated the molecular constraints involved in the T cell immune response to penicillin G (Pen G). Designer peptides containing a DRB1*0401-binding motif and covalently modified with Pen G via a lysine epsilon-amino group were found to induce proliferation of Pen G-specific T cell clones. A precise positioning of the hapten molecule on the peptide backbone was required for optimal T cell recognition. Furthermore, we extended these observations from our designer peptides to show that a peptide sequence derived from a natural DRB1*1101-binding peptide modified in vitro with Pen G, also acquired antigenic properties. Our data for the first time provide insight into the manner in which allergenic haptens are recognized by human T cells involved in allergic reactions to drugs and suggest possible mechanisms leading to the onset of these adverse immune responses.

Penicilloyl peptides are recognized as t cell antigenic determinants in penicillin allergy

Metal ions such as nickel, cobalt, copper and palladium are known to be potent sensitizers in humans, but the antigenic determinants created by these metals as well as the mechanisms of recognition by specific T cell clones are still not elucidated. In this paper, nickel-specific T lymphocyte clones were isolated from four patients exhibiting contact dermatitis to this metal. A panel of 42 independent T cell clones was studied. They were shown to recognize nickel in the context of major histocompatibility complex (MHC) class II molecules and to belong to the CD4 subset. Using fixed autologous Epstein-Barr virus-transformed B cells as antigen-presenting cells (APC), we could distinguish two distinct groups of T cell clones on the basis of processing requirements: 40% of the T cell clones were strictly processing dependent, whereas the remaining 60% could proliferate in response to nickel even in the presence of glutaraldehyde-fixed APC. Furthermore, we present arguments indicating that individual Ni-specific T cell clones cross-react with some transition metals (e.g. Cu or Pd), but not with others (e.g. Co, Cr and Pt), presented by identical MHC class II molecules. These results thus provide an explanation for the multiple metal-reactivities observed in vivo in human patients: they indicate that for Cu and Pd, these co-reactivities in vivo might be due to cross-reactivity at the clonal level. Our findings also suggest that this is not the case for cobalt allergy, which might result from cosensitization of the patient to cobalt in addition to nickel.

Characterization of processing requirements and metal cross-reactivities in T cell clones from patients with allergic contact dermatitis to nickel.

In spite of high frequencies of metal allergies, the structural basis for major histocompatibility complex (MHC)-restricted metal recognition is among the unanswered questions in the field of T cell activation. For the human T cell clone SE9, we have identified potential Ni contact sites in the T cell receptor (TCR) and the restricting human histocompatibility leukocyte antigen (HLA)-DR structure. The specificity of this HLA-DR-promiscuous VA22/VB17+ TCR is primarily harbored in its alpha chain. Ni reactivity is neither dependent on protein processing in antigen-presenting cells nor affected by the nature of HLA-DR-associated peptides. However, SE9 activation by Ni crucially depends on Tyr29 in CDR1alpha, an N-nucleotide-encoded Tyr94 in CDR3alpha, and a conserved His81 in the HLA-DR beta chain. These data indicate that labile, nonactivating complexes between the SE9 TCR and most HLA-DR/peptide conjugates might supply sterically optimized coordination sites for Ni ions, three of which were identified in this study. In such complexes Ni may effectively bridge the TCR alpha chain to His81 of most DR molecules. Thus, in analogy to superantigens, Ni may directly link TCR and MHC in a peptide-independent manner. However, unlike superantigens, Ni requires idiotypic, i.e., CDR3alpha-determined TCR amino acids. This new type of TCR-MHC linkage might explain the high frequency of Ni-reactive T cells in the human population.

/pdf/a-new-type-of-metal-recognition-by-human-t-cells-contact-1x2ymq5jw3.pdf

A new type of metal recognition by human T cells: contact residues for peptide-independent bridging of T cell receptor and major histocompatibility complex by nickel.

Hans Ulrich Weltzien

Papers

Cytolytic and membrane-perturbing properties of lysophosphatidylcholine.

T cell immune responses to haptens. Structural models for allergic and autoimmune reactions

Penicilloyl peptides are recognized as t cell antigenic determinants in penicillin allergy

Characterization of processing requirements and metal cross-reactivities in T cell clones from patients with allergic contact dermatitis to nickel.

A new type of metal recognition by human T cells: contact residues for peptide-independent bridging of T cell receptor and major histocompatibility complex by nickel.