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Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2alow NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues., NK cells control SIV infection in secondary lymphoid tissues in the natural host that typically doesn’t progress toward disease. Here the authors show that this control is associated with terminal NK cell differentiation and improved MHC-E-dependent activity lacking in pathogenic SIV infection.

International audience; Natural killer (NK) cells and lymphoid tissue inducer (LTi) cells were discovered more than 40 and 20 years ago, respectively. These two cell types were initially studied for their unique functions in the elimination of infected or transformed cells, and in the development of lymphoid tissues. It took an additional 10 years to realize that NK cells and LTi cells were members of a larger family of innate lymphoid cells (ILCs), whose phenotypes and functions mirror those of T cells. Many mouse models have since been developed to identify and isolate ILCs, map their developmental pathways and characterize their functions. Because of the similarity between ILCs and T cells, this exploration remains a challenge. In spite of this, a broad range of mouse models available to researchers has lead to significant progress in untangling the unique roles of ILCs early in defense, regulation of adaptive immunity and homeostasis. Here, we review these mouse models, and discuss their strengths and limitations.

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-alpha chain and restricting molecule MR1, this population is rare in laboratory mouse strains (approximate to 0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-alpha locus and led to higher usage of the distal V alpha segments, including V alpha 19. We generated a MAIT(hl) congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44(+)) CD4(-)CD8(lo/neg) T cells with tissue-homing properties (CCR6*CCR7(-)). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18R alpha, and IL-12R beta and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptory gamma (R0R gamma t). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIT(hi) congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.

Subsets of dendritic cells (DCs) have been described according to their functions and anatomical locations. Conventional DC subsets are defined by reciprocal expression of CD11b and CD8α in lymphoid tissues (LT), and of CD11b and CD103 in non-LT (NLT). Spleen CD8α+ and dermal CD103+ DCs share a high efficiency for Ag cross-presentation and a developmental dependency on specific transcription factors. However, it is not known whether all NLT-derived CD103+ DCs and LT-resident CD8α+ DCs are similar despite their different anatomical locations. XCR1 was previously described as exclusively expressed on mouse spleen CD8α+ DCs and human blood BDCA3+ DCs. In this article, we showed that LT-resident CD8α+ DCs and NLT-derived CD103+ DCs specifically express XCR1 and are characterized by a unique transcriptional fingerprint, irrespective of their tissue of origin. Therefore, CD8α+ DCs and CD103+ DCs belong to a common DC subset which is unequivocally identified by XCR1 expression throughout the body.

International audience; Intestinal CD8αα intraepithelial T lymphocytes (T-IELs) have a key role in mucosal immunity and, unlike other T cells, were proposed to differentiate locally. In apparent contradiction, these cells were also shown to originate from a wave of thymus migrants colonizing the gut in the first 3 weeks after birth. We here identify previously uncharacterized very immature CD4(-)CD8(-)CD3(-)CD44(+)CD25(int) thymocytes, which have not yet rearranged their T-cell antigen receptor (TCR), as having the capacity to leave the thymus, migrate to the blood, colonize the gut, and reconstitute CD8αα T-IEL, and show that this cell set is fully responsible for the generation of the CD8αα T-IEL pool. Thus, although the thymus may be fundamental for efficient T-cell commitment, CD8αα T-IEL' complete TCR rearrangements and TCR-αβ/γδ lineage commitment must occur in the gut. These results demonstrate a major role of the gut environment as a primary lymphoid organ.

The chronic stage of HIV-1 infection has been extensively described as a slowly evolving phase, in which the virus induces T-cell death slightly faster than the human body is able to recover. In contrast, T-cell and viral replication dynamics during primary infection have been less well studied. Recent studies in the SIV-macaque model and in HIV-positive patients during the acute infection period have highlighted the massive and irreversible depletion of CD4 memory T cells in the mucosa, particularly in the gut. Hence, gut-associated lymphoid tissue (GALT) plays a central role in the early stages of HIV-1 pathogenesis. Due to its particular cytokine expression pattern, GALT may favour the differential replication of certain HIV-1 subtypes during primary infection, particularly of subtype C. This could enhance the chance of a successful transmission. Moreover, these early events taking place in GALT during primary infection have major implications for therapy and vaccine design. (c) 2007 Lippincott Williams & Wilkins

Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow–derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-α and lymphotoxin-α1β2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.

International audience; Anti-CD20 Ab therapy has proven successful for treating B cell malignancies and a number of autoimmune diseases. However, how anti-CD20 Abs operate in vivo to mediate B cell depletion is not fully understood. In particular, the anatomical location, the type of effector cells, and the mechanism underlying anti-CD20 therapy remain uncertain. Here, we found that the liver is a major site for B cell depletion and that recirculation accounts for the decrease in B cell numbers observed in secondary lymphoid organs. Using intravital imaging, we established that, upon anti-CD20 treatment, Kupffer cells (KCs) mediate the abrupt arrest and subsequent engulfment of B cells circulating in the liver sinusoids. KCs were also effective in depleting malignant B cells in a model of spontaneous lymphoma. Our results identify Ab-dependent cellular phagocytosis by KCs as a primary mechanism of anti-CD20 therapy and provide an experimental framework for optimizing the efficacy of therapeutic Abs.

International audience; The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery.

International audience; BACKGROUND: Germination is a key step for successful Bacillus anthracis colonization and systemic dissemination. Few data are available on spore germination in vivo, and the necessity of spore and host cell interactions to initiate germination is unclear. METHODS: To investigate the early interactions between B. anthracis spores and cutaneous tissue, spores were inoculated in an intraperitoneal cell-free device in guinea pigs or into the pinna of mice. Germination and bacterial growth were analyzed through colony-forming unit enumeration and electron microscopy. RESULTS: In the guinea pig model, germination occurred in vivo in the absence of cell contact. Similarly, in the mouse ear, germination started within 15 minutes after inoculation, and germinating spores were found in the absence of surrounding cells. Germination was not observed in macrophage-rich draining lymph nodes, liver, and spleen. Edema and lethal toxin production were not required for germination, as a toxin-deficient strain was as effective as a Sterne-like strain. B. anthracis growth was locally controlled for 6 hours. CONCLUSIONS: Spore germination involving no cell interactions can occur in vivo, suggesting that diffusible germinants or other signals appear sufficient. Different host tissues display drastic differences in germination-triggering capacity. Initial control of bacterial growth suggests a therapeutic means to exploit host innate defenses to hinder B. anthracis colonization.

International audience; Yersinia pestis dissemination in a host is usually studied by enumerating bacteria in the tissues of animals sacrificed at different times. This laborious methodology gives only snapshots of the infection, as the infectious process is not synchronized. In this work we used in vivo bioluminescence imaging (BLI) to follow Y. pestis dissemination during bubonic plague. We first demonstrated that Y. pestis CO92 transformed with pGEN-luxCDABE stably emitted bioluminescence in vitro and in vivo, while retaining full virulence. The light produced from live animals allowed to delineate the infected organs and correlated with bacterial loads, thus validating the BLI tool. We then showed that the first step of the infectious process is a bacterial multiplication at the injection site (linea alba), followed by a colonization of the draining inguinal lymph node(s), and subsequently of the ipsilateral axillary lymph node through a direct connection between the two nodes. A mild bacteremia and an effective filtering of the blood stream by the liver and spleen probably accounted for the early bacterial blood clearance and the simultaneous development of bacterial foci within these organs. The saturation of the filtering capacity of the spleen and liver subsequently led to terminal septicemia. Our results also indicate that secondary lymphoid tissues are the main targets of Y. pestis multiplication and that colonization of other organs occurs essentially at the terminal phase of the disease. Finally, our analysis reveals that the high variability in the kinetics of infection is attributable to the time the bacteria remain confined at the injection site. However, once Y. pestis has reached the draining lymph nodes, the disease progresses extremely rapidly, leading to the invasion of the entire body within two days and to death of the animals. This highlights the extraordinary capacity of Y. pestis to annihilate the host innate immune response.

International audience; Yersinia pestis dissemination in a host is usually studied by enumerating bacteria in the tissues of animals sacrificed at different times. This laborious methodology gives only snapshots of the infection, as the infectious process is not synchronized. In this work we used in vivo bioluminescence imaging (BLI) to follow Y. pestis dissemination during bubonic plague. We first demonstrated that Y. pestis CO92 transformed with pGEN-luxCDABE stably emitted bioluminescence in vitro and in vivo, while retaining full virulence. The light produced from live animals allowed to delineate the infected organs and correlated with bacterial loads, thus validating the BLI tool. We then showed that the first step of the infectious process is a bacterial multiplication at the injection site (linea alba), followed by a colonization of the draining inguinal lymph node(s), and subsequently of the ipsilateral axillary lymph node through a direct connection between the two nodes. A mild bacteremia and an effective filtering of the blood stream by the liver and spleen probably accounted for the early bacterial blood clearance and the simultaneous development of bacterial foci within these organs. The saturation of the filtering capacity of the spleen and liver subsequently led to terminal septicemia. Our results also indicate that secondary lymphoid tissues are the main targets of Y. pestis multiplication and that colonization of other organs occurs essentially at the terminal phase of the disease. Finally, our analysis reveals that the high variability in the kinetics of infection is attributable to the time the bacteria remain confined at the injection site. However, once Y. pestis has reached the draining lymph nodes, the disease progresses extremely rapidly, leading to the invasion of the entire body within two days and to death of the animals. This highlights the extraordinary capacity of Y. pestis to annihilate the host innate immune response.

NKp46 is a cell surface receptor expressed on natural killer (NK) cells, on a minute subset of T cells, and on a population of innate lymphoid cells that produce IL-22 and express the transcription factor retinoid-related orphan receptor (ROR)-γt, referred to as NK cell receptor (NKR) + ROR-γt + cells. Here we describe Nkp46 iCre knock-in mice in which the gene encoding the improved Cre (iCre) recombinase was inserted into the Nkp46 locus. This mouse was used to noninvasively trace cells expressing NKp46 in vivo. Fate mapping experiments demonstrated the stable expression of NKp46 on NK cells and allowed a reappraisal of the sequential steps of NK cell maturation. NKp46 genetic tracing also showed that gut NKR + ROR-γt + and NK cells represent two distinct lineages. In addition, the genetic heterogeneity of liver NK cells was evidenced. Finally, Nkp46 iCre mice also represent a unique mouse model of conditional mutagenesis specifically in NKp46 + cells, paving the way for further developments in the biology of NKp46 + NK, T, and NKR + ROR-γt + cells.

International audience; Recent studies have identified several DC subsets within the mouse skin and showed that functional specialization exists among them. This Viewpoint summarizes recent data on functional specialization of skin DC subsets and integrates this knowledge into a unifying DC classification that emphasizes the similarities between the DC subsets found in both lymphoid and nonlymphoid tissues of several mammalian species.

Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIV mac251 -induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIV mac251 demonstrated comparable levels of SIV mac251 viral replication, similar rates of mucosal and peripheral CD4 + T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIV mac251 coinfected animals versus SIV mac251 singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIV mac251 infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIV mac251 infection.

In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3negCD127+ immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3negCD127+ cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues.

Stromal cells in lymphoid tissues regulate lymphocyte recruitment and survival through the expression of specific chemokines and cytokines. During inflammation, the same signals recruit lymphocytes to the site of injury; however, the “lymphoid” stromal (LS) cells producing these signals remain poorly characterized. We find that mouse inflammatory lesions and tumors develop gp38+ LS cells, in recapitulation of the development of LS cells early during the ontogeny of lymphoid organs and the intestine, and express a set of genes that promotes the development of lymphocyte-permissive tissues. These gp38+ LS cells are induced by a robust pathway that requires myeloid cells but not known Toll- or NOD-like receptors, the inflammasome, or adaptive immunity. Parabiosis and inducible genetic cell fate mapping experiments indicate that local precursors, presumably resident fibroblasts rather that circulating precursors, massively proliferate and give rise to LS cells during inflammation. Our results show that LS cells are both programmed during ontogeny and reinduced during inflammation.

Background & Aims Retinoic acid (RA) is a crucial factor for maintaining homeostasis in the gut, including lymphocyte homing, immunoglobulin (Ig) A production, and T regulatory cells (Treg) and T helper cell 17 (T H 17) generation. Until now, most attention has focused on the function of dendritic cells (DCs) to initiate adaptive immunity including T and B lymphocytes through RA. To investigate the effects of RA on DCs of gut-associated lymphoid tissue (GALT), we analyzed the phenotype and function of DC subsets from GALT of vitamin A-deficient (VAD) mice. Method VAD mice were prepared by feeding them a VAD diet over 12 weeks from gestational days 10–14. Results Here, we report that tremendous increase of langerin + DCs occurred in the mesenteric lymph nodes (MLNs) and gut lamina propria of VAD mice dependent on CCR7 signaling. Langerin + DCs have phenotypes more similar to those of bone marrow-derived dermal langerin + DCs than epidermal Langerhans cells. Moreover, RA receptor antagonists enhance the differentiation of langerin + DCs from mouse and human precursors of bone marrow and peripheral blood. Langerin + DCs were highly differentiated but less inflammatory than langerin − DCs of MLNs of VAD mice. Moreover, tolerance to orally delivered antigen was completely abrogated by depletion of langerin + DCs in the VAD mice. Conclusions These results suggest that generation of langerin + DCs in the GALT is tightly regulated by RA and that the microenvironment of tissues determines the phenotype of DCs.

National audience; Teleosts, the modern branch of bony fishes, make up the richest group among Vertebrates with more than 20.000 species displaying considerable diversity and found in all aquatic biota. The basal position of fish in vertebrate phylogeny makes them very attractive for genomic and functional comparative studies, especially of the immune system. Although the rapid evolution of proteins involved in immunity and the tumultuous history of fish genomes often obscure the identification of orthologous genes, these studies have demonstrated that the essential components of the mammalian immune system (macrophages, B and T lymphocytes whose receptors undergo V(D)J recombination, MHC, CDs, cytokines, interferon pathway...) are present in fish. The discovery of fundamental immune mechanisms in fish uncovers the primordial vertebrate immune repertoire ; while some unique adaptations also illustrate how a group undergoing adaptative radiation may innovate, drawing on the available genomic resources, in response to specific constraints.

The events that contribute to the progression to AIDS during the acute phase of a primate lentiviral infection are still poorly understood. In this study, we used pathogenic and nonpathogenic simian models of simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between apoptosis in lymph nodes and the extent of viral replication, immune activation, and disease outcome. Here, we show that, in SIVmac251-infected RMs, a marked increased in lymphocyte apoptosis is evident during primary infection at the level of lymph nodes. Interestingly, the levels of apoptosis correlated with the extent of viral replication and the rate of disease progression to AIDS, with higher apoptosis in RMs of Indian genetic background than in those of Chinese origin. In stark contrast, no changes in the levels of lymphocyte apoptosis were observed during primary infection in the nonpathogenic model of SIVagm-sab infection of AGMs, despite similarly high rates of viral replication. A further and early divergence between SIV-infected RMs and AGMs was observed in terms of the dynamics of T- and B-cell proliferation in lymph nodes, with RMs showing significantly higher levels of cycling cells (Ki67+) in the T-cell zones in association with relatively low levels of Ki67+in the B-cell zones, whereas AGMs displayed a low frequency of Ki67+in the T-cell area but a high proportion of Ki67+cells in the B-cell area. As such, this study suggests that species-specific host factors determine an early immune response to SIV that predominantly involves either cellular or humoral immunity in RMs and AGMs, respectively. Taken together, these data are consistent with the hypotheses that (i) high levels of T-cell activation and lymphocyte apoptosis are key pathogenic factors during pathogenic SIV infection of RMs and (ii) low T-cell activation and apoptosis are determinants of the AIDS resistance of SIVagm-infected AGMs, despite high levels of SIVagm replication.

International audience; C1q-deficient and complement depleted mice are highly resistant to intraperitoneal scrapie infection. The molecular mechanisms of complement involvement in scrapie pathogenesis remain unclear. Previous detailed studies have indicated mouse prion protein interactions with human C1q but the question of subsequent complement activation has remained unaddressed. In this investigation, murine prion protein, both recombinant and also from diseased tissue sources, directly activated and fixed complement via the classical but not the alternative pathway. The importance of complexed cupric ions was observed. In addition, evidence of IgG-independent C4 fixation by prion proteins was also shown. Surface plasmon resonance binding studies using variously clustered immobilized recombinant mouse prion protein indicated strong interactions with both purified mouse C1q and also mouse Factor H. Binding, especially by C1q, was dependent upon the volume of immobilized prion protein, suggesting a threshold of clustering density required to support strong interactions. Furthermore, clustered immobilized prion protein appeared capable of promoting polymerization of soluble-phase monomeric prion protein. Direct covalent attachment of complement components to prion proteins via classical pathway activation illustrates a potential mechanism underpinning their trafficking to, and subsequent propagation within, lymphoid tissues.

The predominant path of immunoglobulin class switch recombination follows the paradigm of intra-chromosomal deletion enabling expression of another heavy chain instead of micro and delta. This was, however, challenged by observations of inter-allelic class switch recombination in rabbit or mouse IgG3- or IgA-producing B cells. Assuming that the conditions of inter-chromosomal exchange are likely present at any target S regions in stimulated B cells, we explored trans-association of VH and C genes in a model allowing all C genes to be checked simultaneously. Heterozygous mutant mice are thus studied, which carry one non-functional IgH allele inactivated by a non-translatable mutation of VDJ-CH transcripts, while the functional allele is deficient for class switching due to a truncated 3'regulatory region. A fair level of switching to all Ig classes is restored in heterozygous mice despite the fact that cis-recombination is either non productive on one allele or deficient on the other. Molecular evidence at the DNA level of trans-CSR to IgG3 was demonstrated by cloning and sequencing Smu-Sgamma3 hybrid junctions. These data demonstrate that inter-allelic recombination may broadly rescue the production of various class-switched isotypes and allow complementation between mutations located at both ends of the IgH constant gene cluster.

International audience; Development of Peyer's patches and lymph nodes requires the interaction between CD4+ CD3- IL-7Ralpha+ lymphoid-tissue inducer (LTi) and VCAM-1+ organizer cells. Here we showed that by promoting their survival, enhanced expression of interleukin-7 (IL-7) in transgenic mice resulted in accumulation of LTi cells. With increased IL-7 availability, de novo formation of VCAM-1+ Peyer's patch anlagen occurred along the entire fetal gut resulting in a 5-fold increase in Peyer's patch numbers. IL-7 overexpression also led to formation of multiple organized ectopic lymph nodes and cecal patches. After immunization, ectopic lymph nodes developed normal T cell-dependent B cell responses and germinal centers. Mice overexpressing IL-7 but lacking either RORgamma, a factor required for LTi cell generation, or lymphotoxin alpha1beta2 had neither Peyer's patches nor ectopic lymph nodes. Therefore, by controlling LTi cell numbers, IL-7 can regulate the formation of both normal and ectopic lymphoid organs.

International audience

International audience; In human and murine lymphoid organs, circulating 3 beta-hydroxysteroids, including pregnenolone (PREG), dehydroepiandrosterone (DHEA), and epiandrosterone (EPIA), are 7 alpha-hydroxylated by a cytochrome P450 identified in the hippocampus as P4507B1. Mouse and human lymphoid organs produced different patterns of 3 beta-hydroxysteroid 7 alpha-hydroxylation with the absence of pregnenolone and epiandrosterone hydroxylation in human and mouse, respectively. Both 7 alpha-hydroxy-DHEA and 7 alpha-hydroxy-EPIA triggered a significant increase of antitetanus toxoid and anti-Bordetella pertussis toxins IgGs production in cultures of activated B + T cells derived from human tonsils, whereas both 7 alpha-hydroxy-PREG and 7 alpha-hydroxy-DHEA increased the immune response in mouse. Paracrine action of 7 alpha-hydroxysteroids resulted from their production in cells of the lymphoid organs. Comparison of P4507B1 sequences in rat, human, and two mouse species showed that one amino acid change might explain important differences in KM for 7 alpha-hydroxylation, and suggested that such differences might contribute to the extent of immune response.

International audience; The authors describe the immunological profile of BALB/c mice with Mite-Associated Ulcerative Dermatitis (MAUD)-like disease, due to Myocoptes musculinus (Koch 1844) infestation. The disease probably involves allergic mechanisms and is characterized by erythematous and pruritic skin lesions, widespread hair loss, lymphadenopathy, lymphocytopenia, granulocytosis and wasting. Affected individuals had much reduced numbers of pre-B and B cells in bone marrow and B cells in blood; decreased T-cell numbers in peripheral lymphoid organs and blood; hypergammaglobulinaemia with selective increases of IgG1, IgE and IgA, and depletion on IgM and IgG3, the same isotype distribution being detected in splenic plasmocytes; qualitative modifications of the serum antibody reactivity pattern; and increased production of IL-4 with decreased IL-2 production after in vitro polyclonal stimulation of T cells. Taken together, these results suggest that infestation by M. musculinus in BALB/c mice leads to a significant immunological disorder resulting in a T-helper-2 (Th-2) type response, with marked systemic consequences. This pathological condition may thus provide a useful model system for the immunobiological perturbation associated with chronic allergic disease.