Modulation of testicular macrophage activity by collagenase

Testicular macrophages (TMs) are located in the interstitial tissue of male gonad. These phagocytic cells take part in forming the organ-specific functional blood-testis barrier and participate in the regulation of the local hormonal balance. In the present study, we isolated TMs from testicular tissues using previously described methods - mechanical (M-TMs) or enzymatic, by treatment with collagenase (E-TMs) and then we studied production by these cells of several cytokines and reactive oxygen intermediates (ROI’s). Similarly treated oil-induced peritoneal macrophages (PMs) were used as control cells. PMs had a higher baseline level of production of TNF-α, IL-6, IL-10 and IL-12 than M-TMs and collagenase treatment increased the production of these cytokines (except IL-12) by both cell populations. This effect was significantly more expressed in TMs. In contrast to PMs, TMs produced little ROI’s when stimulated by zymosan. We conclude that in the case of local inflammation in the testis, ROI-negative TMs do not contribute to the tissue damage and instead may direct the local immune response into humoral pathway

Orally administered exosomes suppress mouse delayed-type hypersensitivity by delivering miRNA-150 to antigen-primed macrophage APC targeted by exosome-surface anti-peptide antibody light chains

We previously discovered suppressor T cell-derived, antigen (Ag)-specific exosomes inhibiting mouse hapten-induced contact sensitivity effector T cells by targeting antigen-presenting cells (APCs). These suppressive exosomes acted Ag-specifically due to a coating of antibody free light chains (FLC) from Ag-activated B1a cells. Current studies are aimed at determining if similar immune tolerance could be induced in cutaneous delayed-type hypersensitivity (DTH) to the protein Ag (ovalbumin, OVA). Intravenous administration of a high dose of OVA-coupled, syngeneic erythrocytes similarly induced CD3+CD8+ suppressor T cells producing suppressive, miRNA-150-carrying exosomes, also coated with B1a cell-derived, OVA-specific FLC. Simultaneously, OVA-immunized B1a cells produced an exosome subpopulation, originally coated with Ag-specific FLC, that could be rendered suppressive by in vitro association with miRNA-150. Importantly, miRNA-150-carrying exosomes from both suppressor T cells and B1a cells efficiently induced prolonged DTH suppression after single systemic administration into actively immunized mice, with the strongest effect observed after oral treatment. Current studies also showed that OVA-specific FLC on suppressive exosomes bind OVA peptides suggesting that exosome-coating FLC target APCs by binding to peptide-Ag-major histocompatibility complexes. This renders APCs capable of inhibiting DTH effector T cells. Thus, our studies describe a novel immune tolerance mechanism mediated by FLC-coated, Ag-specific, miRNA-150-carrying exosomes that act on the APC and are particularly effective after oral administration

Gout in the course of systemic lupus erythematosus: Literature review and case study report

Gout is one of the relatively common inflammatory diseases of the joints. It is caused by the deposition of uric acid crystals in the tissues, which induces an acute or chronic inflammatory process. Elevated serum uric acid levels are usually found long before symptoms appear, and it is worth emphasizing that not every hyperuricemic patient will ever develop gout symptoms. The onset of gout is characterized by periodic joint inflammation, which may be triggered by various stress factors (trauma, infection), certain medications, dietary mistakes, and excessive exercise. Over time, repeated joint inflammation causes permanent joint damage. Most often, deposits of urate crystals are located in places with poorer blood supply and exposed to increased pressure, such as joints and soft tissues (e.g., auricles). The coexistence of gout and autoimmune diseases is relatively rare. While for many years it was believed that gout was not associated with other systemic connective tissue diseases, gout has been described in the course of systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. The presented systematic review also describes a case of a patient with longlasting systemic lupus erythematosus who was diagnosed with gout.Gout is one of the relatively common inflammatory diseases of the joints. It is caused by the deposition of uric acid crystals in the tissues, which induces an acute or chronic inflammatory process. Elevated serum uric acid levels are usually found long before symptoms appear, and it is worth emphasizing that not every hyperuricemic patient will ever develop gout symptoms. The onset of gout is characterized by periodic joint inflammation, which may be triggered by various stress factors (trauma, infection), certain medications, dietary mistakes, and excessive exercise. Over time, repeated joint inflammation causes permanent joint damage. Most often, deposits of urate crystals are located in places with poorer blood supply and exposed to increased pressure, such as joints and soft tissues (e.g., auricles). The coexistence of gout and autoimmune diseases is relatively rare. While for many years it was believed that gout was not associated with other systemic connective tissue diseases, gout has been described in the course of systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. The presented systematic review also describes a case of a patient with longlasting systemic lupus erythematosus who was diagnosed with gout

Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity

Background: T-cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles. Objective: We sought to determine the mechanism or mechanisms of immune suppression mediated by the nanovesicles. Methods: T-cell tolerance was induced by means of intravenous injection of hapten conjugated to self-antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated from the tolerized mice for testing in active and adoptive cell-transfer models of CS. Results: Tolerance was shown due to exosome-like nanovesicles in the supernatants of CD81 suppressor T cells that were not regulatory T cells. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains or possibly whole antibody, allowing targeted delivery of selected inhibitory microRNA (miRNA)–150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin-deficient JH2/2 or miRNA-1502/2 mice that produced nonsuppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively. Conclusions: This is the first example of T-cell regulation through systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains

What the immune system is recognizing : towards the new paradigm

Individuals are protected against infections by two mechanisms. The first one non-specific, innate immunity which provides an early protection and is executed mainly by phagocytic cells, and the later one developing specific adoptive immunity which depends on B and T lymphocytes equipped in clonally distributed antigen-specific receptors. T cells recognize an antigen only when presented by the antigen presenting cells (APC), i.e. B lymphocytes, macrophages or dendritic cells (APC) (Signal I). APCs in turn produce an array of different mediators that stimulate T cells to perform their antigen-specific functions (Signal II). As shown by C. A. Janeway, APCs produce Signal II only upon recognition of highly conserved structures (patterns) on the surface of pathogens (PAMPs) by cell-membrane bound non-clonal wide-specific receptors (PRR) (e.g. toll-like receptors, TLR). Only then they decide whether the specific immune response will be induced at all, and also determine the type of effector mechanisms (humoral or cellular). In the "danger hypothesis" by P. Matzinger, more important than recognition of a foreign antigen is recognition of danger signals produced by cells exposed to different kinds of stress (e.g. heat shock proteins, HSP). These signals then activate APCs that, in turn, present antigen to lymphocytes. Antigens that do not cause cell damage (including also some bacterial antigens) are non-immunogenic. Moreover, the effector mechanisms triggered by an antigen are determined not by the antigen itself but by signals flowing from tissues in which antigen is recognized. These models are not mutually exclusive. The integrative hypothesis stresses the role of both microbial products and endogenous macromolecules in activation of the immune surveillance