Keynote Conference - Interevent

Symp#16 Inflammation
Chair Patrícia Bozza
Patrícia Bozza
Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil
Introductory notes
The intimate link between fibrosis and inflammatory response
Niels Olsen Saraiva Camara
Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
Toll-like receptors (TLRs) are an innate family of receptors that can sense tissue damage and orchestrate a cascade of
inflammation. Recent reports have shown reduced fibrosis in TLR4-deficient mice. TLR2 and TLR4 signal via the
intracellular adaptor molecule MyD88, although only few studies implicated a role for MyD88 in fibrosis. TLRs
modulate the immune system through the production of different cytokines and influence fibrosis. In fact, fibrosis is
strongly linked with the development of a Th2-biased response (involving IL4, IL5 and IL13). Macrophages are
considered to play a pivotal role in the development of fibrosis. Recent studies raise the possibility that the effector
phenotype of the recruited macrophages, rather than their presence, determines the extent of renal parenchymal
injury. Macrophages are classified in distinct subpopulations according to their response to innate or adaptive immune
signals. The term “classically activated” has been used to designate the effector macrophages that are produced
during cell-mediated immune responses. Such macrophages are also designated M1 macrophages and express iNOS,
CXCL9, CCR7, CXCL11, IL12 and IFNγ. On the other hand, one of the first innate signals released during tissue injury is
thought to be IL4, an inducer of “alternatively activated” or M2 macrophages. Since collagen deposition is a hallmark
of all chronic diseases, preceded by the development of sterile inflammation, which can be modulated by the presence
of cytokines, here, we present data that MyD88-depend pathway could be involved in sensing these tissue alterations
and in favoring a Th2-prone pro-fibrotic immune response.
How a Parasite MIF Suppresses T cell Immunity and Influenced the Evolution of Macrophage Responsiveness
Rick Bucala MD PhD, Yale University, New Haven, CT.
The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and an
inadequate T cell response may contribute to persistent blood stage infection. We observed that high levels of
inflammatory cytokines inhibit Plasmodium-specific memory T cell development and result in fewer protective
memory T cells. The Plasmodium ortholog of macrophage migration inhibitory factor (MIF), which is produced during
infection, is associated with inflammatory sequelae in human malaria and induces high levels of pro-inflammatory
cytokine expression. Using a genetically targeted strain of P. berghei, the Plasmodium MIF (PMIF) mediated increase in
inflammatory cytokine expression was found to promote T cell apoptosis, resulting in fewer antigen-experienced CD4 T
cells that become memory cells. CD4 T cells activated in the presence of PMIF fail to produce robust anti-malaria recall
responses during a secondary challenge infection and are unable to control parasitemia. These results indicate that
Plasmodia modulate the adaptive immune response and interfere with the generation of malaria-specific memory CD4
T cells, thereby facilitating parasite persistence and transmission. The immunoregulatory function of PMIF may
account for its expression across all Plasmodium spp., its evolutionary conservation in protozoan and helminthic
parasites, and the prevalence of low expression MIF alleles in many human populations. Targeting PMIF may be a
useful approach for augmenting natural host immunity and for producing more effective vaccines.
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