A Conduit to Amplify Innate Immunity
Authors: Christine Moussion, Michael Sixt
Journal: Immunity (2013)

In this issue of Immunity, Py et al., 2013Py B.F. Gonzalez S.F. Long K. Kim S. Kim Y.-A. Zhu H. Yao J. Degauque N. Villet R. Ymele-Leki P. et al.Immunity. 2013; 38 (this issue): 1063-1072Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar report that upon bacterial infection, a fragment of the matrix protein cochlin is released from the conduits of B cell follicles to trigger protective cytokines in the periphery. In this issue of Immunity, Py et al., 2013Py B.F. Gonzalez S.F. Long K. Kim S. Kim Y.-A. Zhu H. Yao J. Degauque N. Villet R. Ymele-Leki P. et al.Immunity. 2013; 38 (this issue): 1063-1072Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar report that upon bacterial infection, a fragment of the matrix protein cochlin is released from the conduits of B cell follicles to trigger protective cytokines in the periphery. Secondary lymphoid organs (SLOs) are linked into the two fluid transport systems of mammals and serve as filters where washed-up pathogenic factors are trapped and examined by immune cells. Lymph nodes clean the interstitial fluid by connecting to the lymphatic vessels while the spleen services the blood circulation. Although SLOs primarily serve adaptive immunity, they also have important innate functions. These are mainly associated with the subcapsular sinus of the lymph node and the marginal zone of the spleen. Both are directly exposed to the fluid phase with all its potentially pathogenic substances and endogenous signals. In these prefilters, innate cells capture particles to either directly eliminate them or to physically carry them into the parenchyma where they are presented or passed on to other cells (Batista and Harwood, 2009Batista F.D. Harwood N.E. Nat. Rev. Immunol. 2009; 9: 15-27Crossref PubMed Scopus (481) Google Scholar). In contrast to the sinuses, where even large particles percolate through the wide interstitial space, the T and B zones are largely shielded from the body fluids. Here, only small solutes below 70 kD have access. And even these do not directly bathe the lymphocytes but exclusively trickle through a highly specialized interstitial compartment, the conduit system (Gretz et al., 2000Gretz J.E. Norbury C.C. Anderson A.O. Proudfoot A.E. Shaw S. J. Exp. Med. 2000; 192: 1425-1440Crossref PubMed Scopus (477) Google Scholar). Conduits are constituted by nonhematopoietic cells, which form a web of delicate and highly interconnected tubules. Each tubule consists of a core of fibrillar extracellular matrix, which is enwrapped by a basement membrane, which is again enveloped by the stroma cells (Gretz et al., 1997Gretz J.E. Anderson A.O. Shaw S. Immunol. Rev. 1997; 156: 11-24Crossref PubMed Scopus (342) Google Scholar). The conduit system is not tightly sealed and both resident dendritic cells and B cells continuously read out the state of lymph and blood by sampling their content. Once filtered through the conduits, the bulk fluid is directly released back into the blood circulation, establishing a fluid-shunt between lymph and blood at the level of the draining lymph node. Although the functional relevance of the conduit system is still poorly investigated, at least three immunological functions have been proposed: (1) Conduits deliver soluble antigens to resident dendritic cells and B cells. Such antigens might then be presented to induce immunity or tolerance (Itano and Jenkins, 2003Itano A.A. Jenkins M.K. Nat. Immunol. 2003; 4: 733-739Crossref PubMed Scopus (370) Google Scholar; Roozendaal et al., 2009Roozendaal R. Mempel T.R. Pitcher L.A. Gonzalez S.F. Verschoor A. Mebius R.E. von Andrian U.H. Carroll M.C. Immunity. 2009; 30: 264-276Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar; Sixt et al., 2005Sixt M. Kanazawa N. Selg M. Samson T. Roos G. Reinhardt D.P. Pabst R. Lutz M.B. Sorokin L. Immunity. 2005; 22: 19-29Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar). (2) Conduits deliver chemokines from the periphery to the lumen of high endothelial venules, where they enhance lymphocyte recruitment (Palframan et al., 2001Palframan R.T. Jung S. Cheng G. Weninger W. Luo Y. Dorf M. Littman D.R. Rollins B.J. Zweerink H. Rot A. von Andrian U.H. J. Exp. Med. 2001; 194: 1361-1373Crossref PubMed Scopus (461) Google Scholar). (3) Conduits deliver cytokines from the periphery into the parenchyma, where they might signal to resident cells (Gretz et al., 2000Gretz J.E. Norbury C.C. Anderson A.O. Proudfoot A.E. Shaw S. J. Exp. Med. 2000; 192: 1425-1440Crossref PubMed Scopus (477) Google Scholar; Nolte et al., 2003Nolte M.A. Beliën J.A.M. Schadee-Eestermans I. Jansen W. Unger W.W.J. van Rooijen N. Kraal G. Mebius R.E. J. Exp. Med. 2003; 198: 505-512Crossref PubMed Scopus (167) Google Scholar). Notably all these potential immunological functions are input functions where the cells within SLOs receive information, which is generated in the periphery or in the sinuses. Py et al., 2013Py B.F. Gonzalez S.F. Long K. Kim S. Kim Y.-A. Zhu H. Yao J. Degauque N. Villet R. Ymele-Leki P. et al.Immunity. 2013; 38 (this issue): 1063-1072Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar now add a new layer of functionality: an output function of the conduits where an inflammatory mediator is released from the conduit into the circulation to act as a global signal to boost antibacterial immunity (see Figure 1). The authors began by characterizing the function of the extracellular matrix component cochlin. Cochlin is a highly conserved protein with two von Willebrand factor A-like domains (vWFA) that presumably couple it to other interstitial matrix components and an LCCL domain with strong homology to the Limulus factor C, a protein involved in the amplification cascade that drives the pyrogen response of the horseshoe crab. The only function of cochlin known to date was in the inner ear, where cochlin is the main noncollagenous matrix component and dominant mutations cause forms of inherited progressive deafness (Robertson et al., 2008Robertson N.G. Jones S.M. Sivakumaran T.A. Giersch A.B.S. Jurado S.A. Call L.M. Miller C.E. Maison S.F. Liberman M.C. Morton C.C. Hum. Mol. Genet. 2008; 17: 3426-3434Crossref PubMed Scopus (39) Google Scholar). Py et al. found that cochlin specifically localizes to the conduits of B cell follicles in spleen and lymph node. Here it is associated with follicular dendritic cells, which also produce the molecule when cultured in vitro. Cochlin is a component of conduits that is specific for the B cell area conduits and cannot be found in the T cell area. In response to infection or LPS injection, the authors show that the proteolytic enzyme aggrecanase-2 is induced in the B cell follicles and that aggrecanase cleaves the LCCL domain off the two vWFA domains. After cleavage, LCCL is released into the blood circulation while the vWFA domains are left in the conduit. In the circulation, the LCCL domains were detected as two differentially glycosylated polypeptides, which, via unknown pathways, signal to innate immune cells in the periphery and amplify cytokine responses. This cascade of events seems to protect the organism against bacterial threats because the authors show that cochlin-deficient mice suffer reduced survival in response to Staphylococcus and Pseudomonas infections. The same was true when aggracanase was inhibited and the disease aggravating effect of aggrecanase inhibition was partly dependent on the presence of cochlin. Interestingly, the authors could not find any indications that cochlin deficiency also affected adaptive immune responses. This assigns a unique function to follicular dendritic cells, which until now were mainly known for their function in driving B cell responses, especially germinal center reactions. Because they seem to be the cells that produce cochlin and possibly also trigger the release of the cochlin fragments into the periphery, follicular dendritic cells may act as local amplifiers of innate immune responses. The proposed mechanism of signal distribution somewhat resembles acute phase responses, where a local cytokine signal is amplified in the liver, which then sends an endocrine signal to the whole organism. SLO conduits appear as the perfect sites for such a signal relay because all immunologically relevant signaling molecules are funneled through their lumen, while their content is directly drained into the blood circulation. This work identifies a signal distributor function of the conduit system and the release of cochlin fragments might only be one aspect of a whole new operational principle. It is very likely that the lumen of the conduit system harbors a large amount of cytokines. For example, the conduit carries dense arrays of heparan sulfate and other charged residues to potentially immobilize immunoactive factors. Because most of the extracellular signaling molecules bind to connective tissue, the conduit might be a potent store for factors, which can be quickly released into the circulation to act as global signals. Cochlin Produced by Follicular Dendritic Cells Promotes Antibacterial Innate ImmunityPy et al.ImmunityMay 16, 2013In BriefCochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. Full-Text PDF Open Archive