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The Journal of Experimental Medicine Aug 1966The effects of various drugs on chemotaxis of polymorphonuclear leukocytes (PMN's) in vitro and in vivo have been studied. Response of rabbit PMN's in vitro to the...
The effects of various drugs on chemotaxis of polymorphonuclear leukocytes (PMN's) in vitro and in vivo have been studied. Response of rabbit PMN's in vitro to the chemotactic factor of rabbit serum, consisting of an activated protein-protein complex of the fifth and sixth (and probably seventh) components of complement (C'), is suppressed by hydrocortisone, methyl prednisolone, and chloroquine. Drug concentrations causing 50% inhibition of chemotaxis in vitro were found to be: hydrocortisone, 2.9 x 10(-4)M; methly prednisolone, 1.2 x 10(-4)M; and chloroquine 8.5 x 10(-6)M. The hydrocortisone effect on PMN's appeared to be irreversible, since washing of the cells did not restore their chemotactic response. 2, 4-Dinitrophenol (DNP), vitamin A, and endotoxin did not inhibit chemotaxis. Hydrocortisone and chloroquine did block serum C' activity in vitro, but only at substantially higher concentrations. Using the reversed passive Arthus reaction in guinea pigs as a model for chemotaxis in vivo, systemic treatment of animals with hydrocortisone or chloroquine inhibited development of the vasculitis. Circulating antigen and C' were fixed in vascular structures, and serum C' was not perceptibly altered. Nevertheless, PMN infiltrates failed to occur. Local administration of hydrocortisone also prevented influx of PMN's in the Arthus reaction, in spite of the fact that immune reactants were found fixed in the vascular walls. Systemic treatment of guinea pigs with DNP did not diminish the intensity of the Arthus reactions. Phagocytosis of zymosan particles by rabbit PMN's was inhibited by hydrocortisone, methyl prednisolone, and chloroquine, but not by DNP or endotoxin. The concentrations of drugs inhibitory in phagocytosis were substantially higher than those required for inhibition of chemotaxis in vitro. These findings suggest that hydrocortisone and chloroquine inhibit the inflammatory process by preventing the response of leukocytes to chemotactic stimuli.
Topics: Animals; Chemotaxis; Chloroquine; Guinea Pigs; Hydrocortisone; In Vitro Techniques; Leukocytes; Methylprednisolone; Vitamin A
PubMed: 5950689
DOI: 10.1084/jem.124.2.209 -
Annals of the Rheumatic Diseases May 1973
Review
Topics: Animals; Antigen-Antibody Complex; Arthritis; Arthus Reaction; Edema; Fever; Heparin; Histamine H1 Antagonists; Humans; Hydrostatic Pressure; Immune Complex Diseases; Immune System Diseases; Immunoglobulins; Necrosis; Nephritis; Neutrophils; Permeability; Phagocytosis; Serum Sickness; Solubility; Steroids
PubMed: 4146024
DOI: 10.1136/ard.32.3.265 -
European Journal of Immunology Dec 2004The deposition of immune complexes induces an acute inflammatory response with tissue injury. Immune complex-induced tissue injury is mediated by inflammatory cell...
Role of C-C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein-1alpha in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production.
The deposition of immune complexes induces an acute inflammatory response with tissue injury. Immune complex-induced tissue injury is mediated by inflammatory cell infiltration that is highly regulated by multiple chemokines. To assess the role of the chemokine receptors CCR1 and CCR5, and a ligand for these receptors CCL3/macrophage inflammatory protein-1alpha, in this pathogenic process, the reverse passive cutaneous Arthus reaction was induced in mice lacking CCR1, CCR5, or CCL3. Edema was significantly attenuated in CCR1-deficient (CCR1(-/-)) and CCL3(-/-) mice but not CCR5(-/-) mice, compared with wild-type mice. Numbers of infiltrating neutrophils and mast cells were reduced in CCL3(-/-) and CCR1(-/-) mice, respectively, compared with wild-type mice. CCR1 and CCR5 were expressed on neutrophils and mast cells. Remarkably, the intradermal mRNA expression of CCL5/RANTES, another ligand for CCR1 and CCR5, was increased in CCR5(-/-) and CCL3(-/-) mice, compared with wild-type mice, while the cutaneous CCL3 mRNA expression was augmented in CCR1(-/-) and CCR5(-/-) mice. These results indicate that CCR1, CCR5, and CCL3 cooperatively contribute to the cutaneous Arthus reaction, and also suggest that enhanced expression of CCL3 and CCL5 compensates for the loss of CCR1, CCR5, and CCL3 in the reaction.
Topics: Animals; Arthus Reaction; Chemokine CCL3; Chemokine CCL4; Chemokines; Edema; Hemorrhage; Leukocytes; Macrophage Inflammatory Proteins; Mice; Peritoneum; Receptors, CCR1; Receptors, CCR5; Receptors, Chemokine; Time Factors
PubMed: 15517609
DOI: 10.1002/eji.200425426 -
The Journal of Investigative Dermatology Feb 2016Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is...
Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation, and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine and/or paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils may also indirectly, via soluble factors, modulate macrophage CXCL1 expression. Consistent with their distinct cellular origins and localization, only neutralization of CXCL2 but not CXCL1 in the interstitium effectively reduced neutrophil recruitment. In summary, our study establishes that neutrophils are able to self-regulate their own recruitment and responses during IC-mediated inflammation through a CXCL2-driven feed forward loop.
Topics: Animals; Antigen-Antibody Complex; Cells, Cultured; Chemokine CXCL2; Dermatitis; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immune Complex Diseases; Inflammation Mediators; Macrophages; Male; Mast Cells; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; RNA, Messenger
PubMed: 26802238
DOI: 10.1038/JID.2015.410 -
British Journal of Pharmacology Dec 19941. Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an...
Studies on the mechanisms involved in the inflammatory response in a reversed passive Arthus reaction in guinea-pig skin: contribution of neutrophils and endogenous mediators.
1. Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an incompletely understood mechanism, dependent on circulating neutrophils. Neutrophil-dependent oedema formation has been described in the skin of rabbits, rats, hamsters, mice and man. In contrast, we presented evidence in a previous study that local oedema formation induced by i.d. injection of chemoattractants in guinea-pig skin was neutrophil-independent. In the present study, we sought evidence of neutrophil-dependent oedema formation in immune-complex-mediated vasculitis, the reversed passive Arthus (RPA) reaction, in guinea-pig skin. We also investigated whether haemorrhage in the RPA reaction was neutrophil-dependent (as it is in other species) and the role of endogenous mediators of inflammation (prostaglandins, nitric oxide, histamine, PAF and leukotrienes) in contributing to the local inflammatory response. 2. In the RPA reaction, most oedema formation occurred over the first 60 min whereas 111In-neutrophil accumulation was still increasing from 60 to 240 min. The different kinetics of these two events suggested that they may be dissociated. 3. Oedema formation was partially inhibited by a long-acting PAF antagonist (UK-74,505) and an H1 histamine receptor antagonist (mepyramine) but not by a 5-lipoxygenase inhibitor (ZM 230487). A nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) suppressed oedema formation by 68% whereas a cyclo-oxygenase inhibitor suppressed oedema by 27%. 4. 111In-neutrophil accumulation in the RPA reaction was partially suppressed by UK-74,505. In contrast, ZM 230487 was without effect at doses which abrogated arachidonic acid-induced 111In-neutrophil accumulation. 5. The anti-CD18 monoclonal antibody, (mAb) 6.5E F(ab')2, effectively inhibited 111In-neutrophil accumulation induced by PAF, zymosan-activated plasma (ZAP) and in the RPA reaction. However, oedema formation measured in the same sites was not altered. In contrast, oedema formation in the RPA reaction was partially suppressed by 6.5E whole mAb which was 2.5 times more potent than 6.5EF(ab')2 at inhibiting guinea-pig neutrophil adhesion to protein-coated plastic. Haemorrhage induced by PAF and in the RPA reaction was significantly inhibited by 6.5E F(ab')2 pretreatment.6. We conclude that in the RPA reaction in guinea-pig skin, oedema formation is partially neutrophil dependent as assessed by using an anti-CD18 mAb, whereas ZAP-induced oedema formation is neutrophil-independent. Haemorrhage was also dependent on neutrophil accumulation. In addition, our studies support a role for PAF in mediating both oedema formation and "'In-neutrophil accumulation in the RPA reaction. Endogenous release of histamine also appears to be important in mediating oedema formation suggesting that mast cells play a critical role in increases of vascular permeability in inflammatory reactions in guinea-pig skin. Moreover, our results confirm previous findings which suggest a dominant role for nitric oxide in maintaining cutaneous blood flow in the guinea-pig.
Topics: Animals; Anti-Inflammatory Agents; Arthus Reaction; CD18 Antigens; Edema; Guinea Pigs; Histamine H1 Antagonists; Indium Radioisotopes; Inflammation; Inflammation Mediators; Leukocytes; Lipoxygenase Inhibitors; Neutrophils; Nitric Oxide; Platelet Activating Factor; Rabbits; Skin; Zymosan
PubMed: 7889293
DOI: 10.1111/j.1476-5381.1994.tb17148.x -
British Medical Journal Nov 1969
Review
Topics: Antigen-Antibody Reactions; Arthus Reaction; Asthma; Autoantibodies; Humans; Hypersensitivity; Immunoglobulin E; Precipitins; Skin Tests; gamma-Globulins
PubMed: 4195381
DOI: 10.1136/bmj.4.5679.355 -
Journal of Clinical Pathology.... 1972
Review
Topics: Aleutian Mink Disease; Animals; Antibodies, Viral; Antibody Formation; Antigen-Antibody Complex; Arthus Reaction; Chickenpox; Complement System Proteins; Coxsackievirus Infections; Equine Infectious Anemia; Herpes Zoster; Herpesviridae Infections; Horses; Humans; Immunity, Cellular; Immunosuppression Therapy; Lymphocyte Activation; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Macrophages; Measles; Mice; Mink; Virus Diseases; Visna-maedi virus
PubMed: 4376149
DOI: No ID Found -
Clinics in Dermatology 2022Cutaneous leukocytoclastic vasculitis (LCV) has a distinctive clinical and light microscopic presentation; however, the etiologic basis of LCV is varied. Most cases are...
Cutaneous leukocytoclastic vasculitis (LCV) has a distinctive clinical and light microscopic presentation; however, the etiologic basis of LCV is varied. Most cases are attributable to immune complex deposition within a vessel wall and represent an Arthus type III immune complex reaction. The prototypic immunoreactant profile is characterized by granular deposits of components of complement activation in concert with immunoglobulin within the cutaneous vasculature. We encountered nine patients with vasculitic and/or vesiculobullous clinical presentations exhibiting an LCV in association with an immunoreactant profile characterized by homogeneous linear deposits of immunoglobulin along the dermal epidermal junction in a fashion resembling an autoimmune vesiculobullous disease. Among the clinical presentations were palpable purpura, urticarial vasculitis, and vesiculobullous eruptions with supervening purpura. Two patients with Crohn disease presented with classic palpable purpura with biopsy-proven LCV, and direct immunofluorescence (DIF) studies demonstrated linear immunoglobulin G (IgG) with floor localization on the salt-split skin assay. Four patients with systemic lupus erythematosus (SLE) showed purpuric vesiculobullous lesions, with evidence of a neutrophilic interface dermatitis and LCV in three of the four. The remaining patient had urticarial nonbullous lesions showing small-vessel vasculitiswith a neutrophilic interface dermatitis. In all of the patients with SLE, DIF studies showed linear immunoglobulin deposits within the basement membrane zone (BMZ). These constellation of findings clinically, light microscopically, and by immunofluorescence were those of a vasculitic presentation of bullous systemic lupus erythematosus. Two patients had linear IgA disease, which was drug induced in one and paraneoplastic in the other, and the dominant morphology on biopsy in both cases was an LCV. One patient microscopically demonstrated drug-associated and eosinophilic enriched LCV with DIF studies showing striking linear deposits of IgG suggestive of bullous pemphigoid, which was consistent with a vasculitic presentation of drug-induced bullous pemphigoid. In all cases, typical granular vascular immunoglobulin and complement deposition compatible with immune complex mediated vasculitis was observed. It is likely that local immune complexes derived from BMZ antigen bound to antibody are pathogenically relevant. We propose the designation of linear vasculitis for this unique scenario of LCV and linear immunoglobulin epidermal BMZ staining, which in some cases represents a vasculitic presentation of conventional autoimmune vesiculobullous disease.
Topics: Humans; Vasculitis, Leukocytoclastic, Cutaneous; Antigen-Antibody Complex; Vasculitis; Skin; Immunoglobulin G; Urticaria; Dermatitis; Autoimmune Diseases; Basement Membrane; Lupus Erythematosus, Systemic
PubMed: 35907580
DOI: 10.1016/j.clindermatol.2022.07.011 -
The Journal of Experimental Medicine Aug 1997We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation. In this study, we...
We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation. In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model. C5aR- deficient mice exhibit decreased migration of neutrophils and decreased levels of TNF-alpha and interleukin 6 in the peritoneal reverse passive Arthus reaction compared to their wild-type littermates. In the reverse passive Arthus reaction in the skin the C5aR was also required for the full expression of neutrophil influx and edema formation; C5aR-deficient mice showed reduced neutrophil migration and microvascular permeability changes. In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin. These data indicate a dominant role for the C5aR and its ligand in the reverse passive Arthus reaction in the lung and a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury.
Topics: Animals; Antibodies; Antigens, CD; Arthus Reaction; Capillary Permeability; Cell Count; Complement System Proteins; Edema; Gene Targeting; Immune Complex Diseases; Immunoglobulin G; Inflammation; Interleukin-6; Lung; Mice; Mice, Knockout; Neutrophils; Ovalbumin; Peritonitis; Peroxidase; Receptor, Anaphylatoxin C5a; Receptors, Complement; Receptors, Fc; Tumor Necrosis Factor-alpha
PubMed: 9271590
DOI: 10.1084/jem.186.5.749 -
Journal of Immunology (Baltimore, Md. :... Apr 2021Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK...
Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.
Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Anti-Inflammatory Agents; Basophils; Blood Platelets; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Humans; Immunoglobulin E; Kidney; Mast Cells; Mice; Mice, 129 Strain; Nephritis; Pemphigus; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic
PubMed: 33674445
DOI: 10.4049/jimmunol.2001130