Ontogeny of myeloid cells

Granulocytes, monocytes, macrophages, and dendritic cells (DCs) represent a subgroup of leukocytes, collectively called myeloid cells. During the embryonic development of mammalians, myelopoiesis occurs in a stepwise fashion that begins in the yolk sac and ends up in the bone marrow (BM). During this process, these early monocyte progenitors colonize various organs such as the brain, liver, skin, and lungs and differentiate into resident macrophages that will self-maintain throughout life. DCs are constantly replenished from BM precursors but can also arise from monocytes in inflammatory conditions. In this review, we summarize the different types of myeloid cells and discuss new insights into their early origin and development in mice and humans from fetal to adult life. We specifically focus on the function of monocytes, macrophages, and DCs at these different developmental stages and on the intrinsic and environmental influences that may drive these adaptations

Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new?

Juvenile idiopathic arthritis (JIA) is a disease characterized by chronic joint inflammation, caused by a deregulated immune response. In patients with JIA, heat shock proteins (HSPs) are highly expressed in the synovial lining tissues of inflamed joints. HSPs are endogenous proteins that are expressed upon cellular stress and are able to modulate immune responses. In this review, we concentrate on the role of HSPs, especially HSP60, in modulating immune responses in both experimental and human arthritis, with a focus on JIA. We will mainly discuss the tolerogenic immune responses induced by HSPs, which could have a beneficial effect in JIA. Overall, we will discuss the immune modulatory capacity of HSPs, and the underlying mechanisms of HSP60-mediated immune regulation in JIA, and how this can be translated into therapy

Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF

Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac-derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80(hi)CD11b(lo) primitive macrophages and Ly6C(hi)CD11b(hi) fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF-deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued AMF development for weeks, although the resulting AMFs displayed an immature phenotype. This demonstrates that tissue-resident macrophages can also develop from fetal monocytes that adopt a stable phenotype shortly after birth in response to instructive cytokines, and then self-maintain throughout life

Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF

Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac-derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80hiCD11blo primitive macrophages and Ly6ChiCD11bhi fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF-deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued

The role of B cells in carriage and clearance of Mycoplasma pneumoniae from the respiratory tract of mice

Background: Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown. Methods: In this study, we show in a mouse model that Mp persists in the nose after pulmonary infection, similar to humans. Results: Infection of mice enhanced Mp-specific immunoglobulin (Ig) M and IgG levels in serum and bronchoalveolar lavage fluid. However, nasal washes only contained elevated Mp-specific IgA. These differences in Ig compartmentalization correlated with differences in Mp-specific B cell responses between nose- and lung-draining lymphoid tissues. Moreover, transferred Mp-specific serum Igs had no effect on nasal carriage in B cell-deficient μMT mice, whereas this enabled μMT mice to clear pulmonary Mp infection. Conclusions: We report the first evidence that humoral immunity is limited in clearing Mp from the upper respiratory tract

Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF

Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac–derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80(hi)CD11b(lo) primitive macrophages and Ly6C(hi)CD11b(hi) fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF–deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued AMF development for weeks, although the resulting AMFs displayed an immature phenotype. This demonstrates that tissue-resident macrophages can also develop from fetal monocytes that adopt a stable phenotype shortly after birth in response to instructive cytokines, and then self-maintain throughout life

T cell regulation in Juvenile Idiopathic Arthritis : Controlling chronic inflammation by pulling the right strings

Understanding the complex cellular and molecular mechanisms that regulate the immune response remains one of the major challenges in immunology. A key question is how the immune system is regulated in order to control a protective immune response and prevent chronic and destructive immunopathology. Within the adaptive immune system CD4+ T cells are keyplayers in the initiation and orchestration of immune responses. However, there is now increasing evidence that subsets of CD4+ T cells are also important negative regulators. Amongst these, the so-called naturally occurring CD4+CD25+ Tregs and IL-10 producing Tr1 cells are the best characterized. The ability of regulatory T cells (Tregs) to control many facets of the immune response suggests that they might be used as targets for new therapeutic strategies. In the first part of this thesis we explored the presence and functionality of different subsets of Tregs in Juvenile Idiopathic Arthritis (JIA). We identified and characterized self heat shock protein 60 (HSP60) specific T cells (chapter 2) and we studied the frequency, phenotype and functionality of naturally occurring CD4+CD25+ Tregs in JIA patients (chapter 3). Subsequently, we explored the role of human HSP60 in the induction and function of CD4+CD25+ Tregs using PBMC of healthy controls and tried to further classify the human HSP60 specific T cells (chapter 4). In the second part of this thesis we evaluated the safety and effectiveness of Autologous Stem Cell Transplantation (ASCT) for refractory JIA by studying 34 JIA patients transplanted in 9 different transplantation centers within Europe (chapter 5). Furthermore, we explored the mechanisms that are attributable to the induction of tolerance by ASCT and identified CD4+CD25+ Tregs as one of the keyplayers in this induction (chapter 6). Taken together the studies described in this thesis may contribute to our understanding of the pathophysiology of JIA as well as of the physiology of regulatory immune responses in general. We identified different subsets of Tregs as crucial players in the tolerization process. Furthermore, it identified human HSP60 being the first known physiological human antigen, naturally present at inflammatory sites and able to activate Tregs. This knowledge may be pivotal in designing the new immunoregulatory strategies for JIA and other autoimmune diseases

The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment

Yearly more than 15 million babies are born premature (<37 weeks gestational age), accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation can lead to the development of bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes in these preterm neonates. BPD patients have an arrest in alveolar and microvascular development and more frequently develop asthma and early-onset emphysema as they age. Understanding how the alveoli develop, and repair, and regenerate after injury is critical for the development of therapies, as unfortunately there is still no cure for BPD. In this review, we aim to provide an overview of emerging new concepts in the understanding of perinatal lung development and injury from a molecular and cellular point of view and how this is paving the way for new therapeutic options to prevent or treat BPD, as well as a reflection on current treatment procedures