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1.
Proc Natl Acad Sci U S A ; 116(15): 7425-7430, 2019 04 09.
Article in English | MEDLINE | ID: mdl-30910977

ABSTRACT

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella A SiiE-derived peptide with homology to laminin ß1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin ß1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.


Subject(s)
Bone Marrow Cells/immunology , Immunity, Humoral , Immunoglobulin G/immunology , Immunologic Memory , Plasma Cells/immunology , Salmonella/immunology , Animals , Bone Marrow Cells/cytology , Immunoglobulin G/genetics , Laminin/genetics , Laminin/immunology , Mice , Mice, Knockout , Plasma Cells/cytology , Salmonella/genetics
2.
Eur J Immunol ; 49(6): 966-968, 2019 06.
Article in English | MEDLINE | ID: mdl-30673129

ABSTRACT

It is a matter of current debate whether the bone marrow is a hub for circulating memory T lymphocytes and/or the home of resident memory T lymphocytes. Here we demonstrate for CD69+ murine CD8+ , and CD69+ murine and human CD4+ memory T lymphocytes of the bone marrow, making up between 30 and 60% of bone marrow memory T lymphocytes, that they express the gene expression signature of tissue-resident memory T lymphocytes. This suggests that a substantial proportion of bone marrow memory T lymphocytes are resident. It adds to previous evidence that bone marrow memory T cells are resting in terms of mobility and proliferation, and maintain exclusive long-term memory to distinct, systemic antigens.


Subject(s)
Bone Marrow Cells/immunology , Immunologic Memory/immunology , Spleen/immunology , T-Lymphocyte Subsets/immunology , Animals , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Humans , Lectins, C-Type/immunology , Mice , Spleen/cytology , Transcriptome/immunology
3.
Proc Natl Acad Sci U S A ; 115(6): 1334-1339, 2018 02 06.
Article in English | MEDLINE | ID: mdl-29358404

ABSTRACT

The bone marrow maintains memory CD4 T cells, which provide memory to systemic antigens. Here we demonstrate that memory CD4 T cells are reactivated by antigen in the bone marrow. In a secondary immune response, antigen-specific T cells of the bone marrow mobilize and aggregate in immune clusters together with MHC class II-expressing cells, mostly B lymphocytes. They proliferate vigorously and express effector cytokines, but they do not develop into follicular T-helper cells. Neither do the B lymphocytes develop into germinal center B cells in the bone marrow. Within 10 days, the immune clusters disappear again. Within 30 days, the expanded antigen-specific memory CD4 T cells return to memory niches and are maintained again individually as resting cells. Thus, in secondary immune responses in the bone marrow T-cell memory is amplified, while in germinal center reactions of secondary lymphoid organs humoral memory is adapted by affinity maturation.


Subject(s)
Bone Marrow/immunology , CD4-Positive T-Lymphocytes/immunology , Immunologic Memory , Animals , B-Lymphocytes/immunology , Bone Marrow/drug effects , CD4-Positive T-Lymphocytes/cytology , Cell Movement , Cell Proliferation , Fingolimod Hydrochloride/immunology , Fingolimod Hydrochloride/pharmacology , Gene Expression Regulation/immunology , Immunization, Secondary , Immunosuppressive Agents/pharmacology , Lymphocyte Activation , Male , Mice, Inbred C57BL , Receptors, CXCR5/genetics , Receptors, CXCR5/immunology , Spleen/cytology , Spleen/immunology
4.
Arthritis Rheumatol ; 67(4): 1023-35, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25546822

ABSTRACT

OBJECTIVE: The hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. The aim of this study was to investigate whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage in an MRL/lpr mouse model of systemic lupus erythematosus (SLE). METHODS: MRL/lpr mice progressively produce high levels of autoantibodies, and the resultant deposition of immune complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria, assessment of kidney histology, determination of antinuclear antibody (ANA) production and cytokine levels, and flow cytometric analysis of relevant cellular populations. RESULTS: ES-62 restored the disrupted balance between effector and regulatory B cells in MRL/lpr mice by inhibiting plasmablast differentiation, with a consequent reduction in ANA production and deposition of immune complexes and C3a in the kidneys. Moreover, by reducing interleukin-22 production, ES-62 may desensitize downstream effector mechanisms in the pathogenesis of kidney disease. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/lpr mice mimicked the protection afforded by the helminth product. Mechanistically, this reflects down-regulation of myeloid differentiation factor 88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic cross-talk among Toll-like receptor-, C3a-, and immune complex-mediated effector mechanisms. CONCLUSION: This study provides the first demonstration of protection against kidney pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on the mechanism of action of ES-62.


Subject(s)
Antibodies, Antinuclear/biosynthesis , Helminth Proteins/metabolism , Kidney/metabolism , Lupus Erythematosus, Systemic/metabolism , Myeloid Differentiation Factor 88/metabolism , Proteinuria/metabolism , Animals , Disease Models, Animal , Kidney/pathology , Lupus Erythematosus, Systemic/pathology , Mice , Mice, Inbred MRL lpr , Proteinuria/pathology
5.
Proc Natl Acad Sci U S A ; 111(25): 9229-34, 2014 Jun 24.
Article in English | MEDLINE | ID: mdl-24927527

ABSTRACT

In the bone marrow, a population of memory T cells has been described that promotes efficient secondary immune responses and has been considered to be preactivated, owing to its expression of CD69 and CD25. Here we show that human bone marrow professional memory T cells are not activated but are resting in terms of proliferation, transcription, and mobility. They are in the G0 phase of the cell cycle, and their transcriptome is that of resting T cells. The repertoire of CD4(+) bone marrow memory T cells compared with CD4(+) memory T cells from the blood is significantly enriched for T cells specific for cytomegalovirus-pp65 (immunodominant protein), tetanus toxoid, measles, mumps, and rubella. It is not enriched for vaccinia virus and Candida albicans-MP65 (immunodominant protein), typical pathogens of skin and/or mucosa. CD4(+) memory T cells specific for measles are maintained nearly exclusively in the bone marrow. Thus, CD4(+) memory T cells from the bone marrow provide long-term memory for systemic pathogens.


Subject(s)
Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Bone Marrow Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Immunologic Memory/physiology , Interleukin-2 Receptor alpha Subunit/immunology , Lectins, C-Type/immunology , Resting Phase, Cell Cycle/immunology , Adult , Bone Marrow Cells/cytology , CD4-Positive T-Lymphocytes/cytology , Female , Humans , Male , Middle Aged
6.
Immunology ; 141(3): 457-66, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24708419

ABSTRACT

We have previously reported that ES-62, a molecule secreted by the parasitic filarial nematode Acanthocheilonema viteae, protects mice from developing collagen-induced arthritis (CIA). Together with increasing evidence that worm infection may protect against autoimmune conditions, this raises the possibility that ES-62 may have therapeutic potential in rheumatoid arthritis and hence, it is important to fully understand its mechanism of action. To this end, we have established to date that ES-62 protection in CIA is associated with suppressed T helper type 1 (Th1)/Th17 responses, reduced collagen-specific IgG2a antibodies and increased interleukin-10 (IL-10) production by splenocytes. IL-10-producing regulatory B cells have been proposed to suppress pathogenic Th1/Th17 responses in CIA: interestingly therefore, although the levels of IL-10-producing B cells were decreased in the spleens of mice with CIA, ES-62 was found to restore these to the levels found in naive mice. In addition, exposure to ES-62 decreased effector B-cell, particularly plasma cell, infiltration of the joints, and such infiltrating B cells showed dramatically reduced levels of Toll-like receptor 4 and the activation markers, CD80 and CD86. Collectively, this induction of hyporesponsiveness of effector B-cell responses, in the context of the resetting of the levels of IL-10-producing B cells, is suggestive of a modulation of the balance between effector and regulatory B-cell responses that may contribute to ES-62-mediated suppression of CIA-associated inflammation and inhibition of production of pathogenic collagen-specific IgG2a antibodies.


Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Experimental/prevention & control , B-Lymphocytes/drug effects , Collagen , Helminth Proteins/pharmacology , Interleukin-10/metabolism , Joints/drug effects , Plasma Cells/drug effects , Animals , Antibodies/metabolism , Antigens, CD/metabolism , Arthritis, Experimental/blood , Arthritis, Experimental/chemically induced , Arthritis, Experimental/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biomarkers/metabolism , Cells, Cultured , Collagen/immunology , Joints/immunology , Joints/metabolism , Male , Mice , Mice, Inbred DBA , Plasma Cells/immunology , Plasma Cells/metabolism , Spleen/drug effects , Spleen/immunology , Spleen/metabolism , Toll-Like Receptor 4/metabolism
7.
Arthritis Rheum ; 64(10): 3168-78, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22729944

ABSTRACT

OBJECTIVE: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. METHODS: DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. RESULTS: ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17-producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. CONCLUSION: Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.


Subject(s)
Arthritis, Experimental/metabolism , CD4-Positive T-Lymphocytes/drug effects , Dendritic Cells/drug effects , Helminth Proteins/pharmacology , Interleukin-17/metabolism , Animals , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Joints/drug effects , Joints/metabolism , Joints/pathology , Male , Mice , Up-Regulation
8.
Methods Cell Biol ; 102: 231-60, 2011.
Article in English | MEDLINE | ID: mdl-21704841

ABSTRACT

Until recently, it has not been possible to image and functionally correlate the key molecular and cellular events underpinning immunity and tolerance in the intact immune system. Certainly, the field has been revolutionized by the advent of tetramers to identify physiologically relevant specificities of T cells, and the introduction of models in which transgenic T-cell receptor and/or B-cell receptor-bearing lymphocytes are adoptively transferred into normal mice and can then be identified by clonotype-specific antibodies using flow cytometry in vitro, or immunohistochemistry ex vivo. However, these approaches do not allow for quantitative analysis of the precise anatomical, phenotypic, signaling, and functional parameters required for dissecting the development of immune responses in health and disease in vivo. Traditionally, assessment of signal transduction pathways has required biochemical or molecular biological analysis of isolated and highly purified subsets of immune system cells. Inevitably, this creates potential artifacts and does not allow identification of the key signaling events for individual cells present in their microenvironment in situ. These difficulties have now been overcome by new methodologies in cell signaling analysis that are sufficiently sensitive to detect signaling events occurring in individual cells in situ and the development of technologies such as laser scanning cytometry that provide the tools to analyze physiologically relevant interactions between molecules and cells of the innate and the adaptive immune system within their natural environmental niche in vivo.


Subject(s)
Cell Tracking/methods , Immune System/immunology , Laser Scanning Cytometry/methods , Adoptive Transfer , Animals , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Cartilage, Articular/immunology , Cartilage, Articular/pathology , Foot Joints/immunology , Foot Joints/pathology , Humans , Immune System/cytology , Kidney/immunology , Kidney/pathology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/pathology , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphocyte Activation , Mast Cells/immunology , Mast Cells/pathology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Receptors, Antigen, T-Cell/metabolism , Staining and Labeling/methods , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation
9.
Nat Immunol ; 12(4): 344-51, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21358639

ABSTRACT

Sepsis is one of the most challenging health problems worldwide. Here we found that phagocytes from patients with sepsis had considerable upregulation of Toll-like receptor 4 (TLR4) and TLR2; however, shock-inducing inflammatory responses mediated by these TLRs were inhibited by ES-62, an immunomodulator secreted by the filarial nematode Acanthocheilonema viteae. ES-62 subverted TLR4 signaling to block TLR2- and TLR4-driven inflammatory responses via autophagosome-mediated downregulation of the TLR adaptor-transducer MyD88. In vivo, ES-62 protected mice against endotoxic and polymicrobial septic shock by TLR4-mediated induction of autophagy and was protective even when administered after the induction of sepsis. Given that the treatments for septic shock at present are inadequate, the autophagy-dependent mechanism of action by ES-62 might form the basis for urgently needed therapeutic intervention against this life-threatening condition.


Subject(s)
Helminth Proteins/pharmacology , Myeloid Differentiation Factor 88/metabolism , Phagosomes/drug effects , Shock, Septic/prevention & control , Toll-Like Receptor 4/metabolism , Animals , Autophagy/drug effects , Autophagy/immunology , Cells, Cultured , Female , Humans , Immunoblotting , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Macrophages/drug effects , Macrophages/metabolism , Macrophages/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Microscopy, Electron , Myeloid Differentiation Factor 88/immunology , Phagosomes/immunology , Phagosomes/metabolism , Shock, Septic/genetics , Shock, Septic/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , Toll-Like Receptor 2/immunology , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
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