An interview published in Ellipse, the monthly magazine of the PRBB.
Andrea Cerutti is a 44-year old Italian ICREA research professor who joined the IMIM in 2010, after moving from Padua to New York. Here he leads the B-cell laboratory in parallel with his former lab at the Mount Sinai School of Medicine in New York. As an immunologist he aims to understand the basic principles underlying B-cell functions leading to the diversification of antibodies.
Why did you come to Spain?
After 14 years in the USA coming to Spain was not only a scientific, but also a very personal decision. I always felt like a European and wanted to come back. My timing might not have been the best, since I was doing quite well in the USA, while here it is difficult to get funding for our research.
What do the IMIM and the PRBB offer you?
Here we have a unique collaboration with the Hospital del Mar, allowing us access to precious human tissue samples. I also appreciate the scientific surroundings here at the PRBB which offer the possibility of interacting with scientists from many different disciplines.
Do you still do clinical work?
At some point in my career I had to make a decision and I opted for research. In order to work as a physician in the USA, I would have been forced to redo my specialist medical training, which would have taken far too long. I also wanted to continue doing competitive research, and combining work in the clinic and the lab is very difficult.
What has been your major discovery?
Our most important finding was the identification of the antibody-inducing function of the cytokines BAFF and APRIL, which are produced by cells of the innate immune system. This system was thought to be broad and unspecific, but we proved otherwise. BAFF and APRIL are molecules which activate B-cells, resulting in a switch of antibody subclass. This process was thought to happen exclusively in the much slower but more specific adaptive immune system via the interaction of B cells with T-cells. We have recently published the mechanism that explains how the bridging of the innate and adaptive immune systems takes place.
What would be your ideal goal in science?
It would be nice to understand the real nature of B-cell diversity: where they come from; why they have specific characteristics and how they react in different situations. It is known that the source of B-cells is the bone marrow and that some of these naïve precursors are already diverse. However we do not yet understand how and why some B cells produce one specific type of antibody class rather than another.
It would also be fantastic to find a way to develop prophylactic vaccines capable of providing broadly neutralising antibodies against HIV or influenza. Following this idea, one could imagine the creation of a “superantibody” capable of blocking virtually any strain of these continuously changing viruses. However, in order to achieve these goals we must first understand how specific subsets of B-cells work.
Repairing a tissue after an injury requires the infiltration of inflammatory cells and the activation of the resident stem cells, which will restore the damaged tissue. But for full tissue recovery to happen, the inflammation that is first necessary must be resolved. The Myogenesis research group at the CEXS-UPF, led by Pura Muñoz-Cánoves, has recently provided evidence of how this happens.
For the inflammation to disappear, macrophages (a type of immune cells that are involved in the healing of muscle and other tissues) must switch from a pro-inflammatory to an anti-inflammatory phenotype. While it is known that disturbing the interactions between inflammatory cells and tissue resident cells prevents successful healing, the molecular mechanisms underlying the interactions between these cell types are practically unknown.
In an Extra Views article recently published in Cell Cycle, the authors review their work about how macrophages control stem cell-dependent tissue repair. In particular, Muñoz-Cánoves and colleagues demonstrated, in a paper in Journal of Cell Biology, a new function for MAPK phosphatase MKP-1 (MKP-1) in the regulation of p38 MAPK (p38) signaling, which leads to the deactivation of macrophages during inflammation resolution after injury.
At advanced stages of regeneration, MKP-1 loss caused an unscheduled “exhaustion-like” state in muscle macrophages, in which neither pro- nor anti-inflammatory cytokines are expressed despite persistent tissue damage. This leads to reparation by the tissue stem cells.
Because this progressive attenuation of pro-inflammatory gene expression is also involved in the process of tolerance to bacterial infection, the authors discuss the potential similarities between the two mechanisms: inflammation resolution during tissue repair (studied in this work) and endotoxin tolerance.
Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P
p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair.
J Cell Biol. 2011 Oct 17;195(2):307-22
His group, in collaboration with scientists in Mount Sinai in New York, has just discovered the presence of neutrophils in the marginal zone (MZ) of the spleen, a B cell area positioned at the interface between the circulation and the immune system. The presence of these cells is constant, even in the absence of infection.
The authors obtained lymphoid organs from people with no inflammation or infection. Unexpectedly, they detected many neutrophils in the perifollicular area of spleens that had no histological alterations – up to 10% of the total cells in the spleens were neutrophils. They also detected perifollicular neutrophils in spleens from healthy rhesus macaques and mice, suggesting these spleen neutrophils are probably common to all mammals.
They compared this newly found population of neutrophils with the circulating ones, and found they had a distinct phenotype. They also had a different function: they interacted with marginal zone B cells, and elicited immunoglobulin class switching, somatic hypermutation and antibody production by activating those B cells via BAFF and APRIL and the cytokine IL-21 – an immunoregulatory function that is new to neutrophils.
Being strategically located at the interface with the circulation, the major role of the marginal zone is to trap particulate antigen from the circulation and present them to the lymphocytes of the spleen. Marginal zone B cells are therefore geared to rapidly respond to blood-borne antigens. The authors believe that the discovered spleen neutrophils may generate an innate layer of antimicrobial immunoglobulin defense by undergoing B cell–helper reprogramming in the spleen. Actually, they found these ‘B cell–helper neutrophils’ to activate marginal zone B cells as effectively as splenic CD4+ T cells, and more effectively than splenic macrophages or dendritic cells (DCs).
Cerutti and colleagues conclude that an insufficiency of these ‘B cell–helper neutrophils’ could contribute to the pathogenesis of systemic infections in patients with neutrophil disorders. Conversely, harnessing these cells with specific adjuvants may enhance vaccine-induced immunoglobulin responses to poorly immunogenic antigens in healthy people.
Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan M, Xu W, Magri G, Knowles DM, Tam W, Chiu A, Bussel JB, Serrano S, Lorente JA, Bellosillo B, Lloreta J, Juanpere N, Alameda F, Baró T, de Heredia CD, Torán N, Català A, Torrebadell M, Fortuny C, Cusí V, Carreras C, Diaz GA, Blander JM, Farber CM, Silvestri G, Cunningham-Rundles C, Calvillo M, Dufour C, Notarangelo LD, Lougaris V, Plebani A, Casanova JL, Ganal SC, Diefenbach A, Aróstegui JI, Juan M, Yagüe J, Mahlaoui N, Donadieu J, Chen K, & Cerutti A (2011). B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nature immunology PMID: 22197976
The intestinal mucosa has evolved several strategies to control microbic commensals and neutralize pathogens without causing inflammatory damage to the epithelial barrier. One of these strategies involves the production of massive amounts of IgA, the most abundant antibody isotype in our body. The review puts together scientific evidence on the mechanisms by which mucosal B cells undergo IgA diversification and production and discusses how the study of primary immunodeficiencies facilitates better understanding of mucosal IgA responses in humans.
Cerutti A, Cols M, Gentile M, Cassis L, Barra CM, He B, Puga I, Chen K; Regulation of mucosal IgA responses: lessons from primary immunodeficiencies. Ann N Y Acad Sci. 2011 Nov;1238(1):132-44
The immunology group of the Department of Experimental and Health Sciences of the UPF seeks for a candidate to apply to the next Juan de la Cierva Programme call (Ministerio de Ciencia e Innovación). This competitive call of three-year contracts will open for applications around February 2012 and is expected to resolve around June 2012.
Details: Postdoctoral Position in Immunology