FEBS Virtual Issue Immunology

Edited By: Henry Daniell and Keith Edwards

Virtual Issue

Immunology Papers selected by: Peter Parham

Introduction Introduction

Immunology Immunology is the study of the immune system, and the mechanisms by which it cultivates our vast internal populations of commensal organisms while eliminating the occasional invading pathogen.

Microbes evolve quicker than mammals and with time can evade the immune response. Inevitably, the immune system is suboptimal and each human being is destined to suffer from infectious disease throughout their lifetime. On top of this, are the chronic diseases of autoimmunity and allergy, as well as infections that don’t go away, like those caused by HIV and HCV, which arise from either an over zealous or inadequate immune response.

The papers in this virtual issue of the FEBS journal run the temporal gamut of the immune response, from the early secretion of antimicrobial peptides when infection is first detected, through to the formation of terminally differentiated plasma cells whose high affinity antibodies provide the ultimate weapon for shutting down infection for good. In preparing this virtual issue, I endeavoured to sort the papers into two sections corresponding to innate immunity (inflammation) and adaptive immunity (B cells and T cells), a division that has historically served to separate the earlier and later phases of the immune response. But in the end I gave up.

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Article Introduction

Multifunctional host defense peptides: Antimicrobial peptides, the small yet big players in innate and adaptive immunity Constance Auvynet, Yvonne Rosenstein FEBS Journal, Volume 276, Issue 22, November 2009, Pages: 6497–6508

The term ‘antimicrobial peptides’ refers to a large number of peptides first characterized on the basis of their antibiotic and antifungal activities. In addition to their role as endogenous antibiotics, antimicrobial peptides, also called host defense peptides, participate in multiple aspects of immunity (inflammation, wound repair, and regulation of the adaptive immune system) as well as in maintaining homeostasis. The possibility of utilizing these multifunctional molecules to effectively combat the ever-growing group of antibioticresistant pathogens has intensified research aimed at improving their antibiotic activity and therapeutic potential, without the burden of an exacerbated inflammatory response, but conserving their immunomodulatory potential. In this minireview, we focus on the contribution of small cationic antimicrobial peptides – particularly human cathelicidins and defensins – to the immune response and disease, highlighting recent advances in our understanding of the roles of these multifunctional molecules.

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Article Introduction

Cytokine properties of prokineticins Justin Monnier, Michel Samson FEBS Journal, Volume 275, Issue 16, August 2008, Pages: 4014–4021

Prokineticins are a novel family of secreted peptides with diverse regulatory roles, one of which is their capacity to modulate immunity in humans and in other species. Prokineticins are small peptides of 8 kDa that mediate their biological activities by signaling through two homologous G-protein-coupled receptors (prokineticin receptor 1 and prokineticin receptor 2). This family of peptides is characterized by a completely conserved N-terminal hexapeptide crucial for their bioactivities and a unique structural motif comprising five disulfide bonds. Prokineticins and their receptors are highly expressed in bone marrow, in peripheral circulating leukocytes, in inflamed tissues and in resident organ immune cells. Their structure, size, signaling and biological activities are reminiscent of the chemokine superfamily. In this review, emphasis is placed on the properties of prokineticins as cytokines and their role in the immune system.

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Article Introduction

CD91 interacts with mannan-binding lectin (MBL) through the MBLassociated serine proteases binding site Karen Duus, Nicole M. Thielens, Monique Lacroix, Pascale Tacnet, Philippe Frachet, Uffe Holmskov, Gunnar Houen FEBS Journal, Volume 277, Issue 23, December 2010, Pages: 4956-4964

CD91 plays an important role in the scavenging of apoptotic material, possibly through binding to soluble pattern-recognition molecules. In this study, we investigated the interaction of CD91 with mannanbinding lectin (MBL), ficolins and lung surfactant proteins. Both MBL and L-ficolin were found to bind CD91. The MBL–CD91 interaction was time- and concentration-dependent and could be inhibited by known ligands of CD91. MBL-associated serine protease 3 (MASP-3) also inhibited binding between MBL and CD91, suggesting that the site of interaction is located at or near the MASP–MBL interaction site. This was confirmed by using MBL mutants deficient for MASP binding that were unable to interact with CD91. These findings demonstrate that MBL and L-ficolin interact with CD91, strongly suggesting that they have the potential to function as soluble recognition molecules for scavenging microbial and apoptotic material by CD91.

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Article Introduction

Direct interaction between CD91 and C1q Karen Duus, Erik W. Hansen, Pascale Tacnet, Philippe Frachet, Gerard J. Arlaud, Nicole M. Thielens, Gunnar Houen FEBS Journal, Volume 277, Issue 17, September 2010, Pages: 3526–3537

C1q-mediated removal of immune complexes and apoptotic cells plays an important role in tissue homeostasis and the prevention of autoimmune conditions. It has been suggested that C1q mediates phagocytosis of apoptotic cells through a receptor complex assembled from CD91 (α-2- macroglobulin receptor, or low-density lipoprotein receptor-related protein) and calreticulin, with CD91 being the transmembrane part and calreticulin acting as the C1qbinding molecule. In the present study, we observe that C1q binds cells from a CD91 expressing monocytic cell line as well as monocytes from human blood. C1q binding to monocytes was shown to be correlated with CD91 expression and could be inhibited by the CD91 chaperone, receptor-associated protein. We also report data showing a direct interaction between CD91 and C1q. The interaction was investigated using various protein interaction assays. A direct interaction between purified C1q and CD91 was observed both by ELISA and a surface plasmon resonance assay, with either C1q or CD91 immobilized. The interaction showed characteristics of specificity because it was time-dependent, saturable and could be inhibited by known ligands of both CD91 and C1q. The results obtained show for the first time that CD91 recognizes C1q directly. On the basis of these findings, we propose that CD91 is a receptor for C1q and that this multifunctional scavenger receptor uses a subset of its ligandbinding sites for clearance of C1q and C1q bound material.

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Article Introduction

Human lactoferrin activates NF-κB through Toll-like receptor 4 (TLR4) pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling Ken Ando, Keiichi Hasegawa, Ken-ichi Shindo, Tomoyasu Furusawa, Tomofumi Fujino, et al.

FEBS Journal, Volume 277, Issue 9, May 2010, Pages: 2051–2066

Lactoferrin (LF) has been implicated in innate immunity. Here we reveal the signal transduction pathway responsible for human LF (hLF)-triggered nuclear factor-κB (NF-κB) activation. Endotoxindepleted hLF induces NF-κB activation at physiologically relevant concentrations in the human monocytic leukemia cell line, THP-1, and in mouse embryonic fibroblasts (MEFs). In MEFs, in which both tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 are deficient, hLF causes NF-κB activation at a level comparable to that seen in wild-type MEFs, whereas TRAF6deficient MEFs show significantly impaired NF-κB activation in response to hLF. TRAF6 is known to be indispensable in leading to NF-κB activation in myeloid differentiating factor 88 (MyD88)dependent signaling pathways, while the role of TRAF6 in the MyD88-independent signaling pathway has not been clarified extensively. When we examined the hLF-dependent NF-κB activation in MyD88-deficient MEFs, delayed, but remarkable, NFκB activation occurred as a result of the treatment of cells with hLF, indicating that both MyD88-dependent and MyD88-independent pathways are involved. Indeed, hLF fails to activate NF-κB in MEFs lacking Toll-like receptor 4 (TLR4), a unique TLR group member that triggers both MyD88-depependent and MyD88-independent signalings.

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