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The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)–mediated activation of mast cells and basophils, IgG (FcγR)–mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

Zizyphus mauritiana Lam. seeds (ZMS) have been used medicinally as sedative or hypnotic drugs in most of Asian countries. ZMS has significant benefits to the human health. Therefore, we have evaluated immunomodulatory effect of lectin extracted from these ZMSL in both in vitro and in vivo study. Anaphylaxis is a severe life-threatening allergic reaction and Arthus reaction is deposition of immune complex and complement system activation, so we hypothesized that if ZMSL can protect these severe allergic diseases. We have studied the effect of ZMSL on macrophages and Wistar albino rats and confirmed its protective effect against anaphylaxis and Arthus reaction. Results of this study suggest ZMSL have immunostimulatory and antiallergic activity.

Although neutrophils play important roles in immunity and inflammation, their analysis is strongly hindered by their short-lived and terminally differentiated nature. Prior studies reported conditional immortalization of myeloid progenitors using retroviral expression of an estrogen-dependent fusion protein of the HoxB8 transcription factor. This approach allowed the long-term culture of mouse myeloid progenitors (HoxB8 progenitors) in estrogen-containing media, followed by differentiation toward neutrophils upon estrogen withdrawal. Although several reports confirmed the in vitro functional responsiveness of the resulting differentiated cells (HoxB8 neutrophils), little is known about their capacity to perform in vivo neutrophil functions. We have addressed this issue by an in vivo transplantation approach. In vitro–generated HoxB8 neutrophils showed a neutrophil-like phenotype and were able to perform conventional neutrophil functions, like respiratory burst, chemotaxis, and phagocytosis. The i.v. injection of HoxB8 progenitors into lethally irradiated recipients resulted in the appearance of circulating donor-derived HoxB8 neutrophils. In vivo–differentiated HoxB8 neutrophils were able to migrate to the inflamed peritoneum and to phagocytose heat-killed Candida particles. The reverse passive Arthus reaction could be induced in HoxB8 chimeras but not in irradiated, nontransplanted control animals. Repeated injection of HoxB8 progenitors also allowed us to maintain stable circulating HoxB8 neutrophil counts for several days. Injection of arthritogenic K/B×N serum triggered robust arthritis in HoxB8 chimeras, but not in irradiated, nontransplanted control mice. Taken together, our results indicate that HoxB8 progenitor–derived neutrophils are capable of performing various in vivo neutrophil functions, providing a framework for using the HoxB8 system for the in vivo analysis of neutrophil function.

The formation and deposition of immune complexes (IC) containing immunoglobulin (Ig)G antibodies induces an acute inflammatory response with tissue injury. One of the experimental models of IC-related vasculitis is the cutaneous reverse passive Arthus reaction, in which IgG antibodies are injected i.d., followed immediately by the i.v. application of the corresponding antigen. This reaction is characterized by edema, hemorrhage and neutrophil infiltration. To assess the role of the anti-inflammatory cytokine interleukin (IL)-10 in IC-related vasculitis, we investigated the cutaneous Arthus reaction using IL-10 knockout (IL-10KO) mice. Edema, which was quantified macroscopically by measuring the vascular leakage of Evans blue dye at 4 h after IC challenge, was significantly increased in IL-10KO mice compared with wild-type mice. In addition, hemorrhage, which was assessed by the average diameter of purpuric spots at 8 h after IC challenge, was enhanced significantly in IL-10KO mice compared with wild-type mice. Histological examination showed that the number of extravascular neutrophils was significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. Analysis of pro-inflammatory cytokine mRNA expression showed that IL-6 mRNA levels were significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. These results showed that IC-induced inflammation and vascular damage were significantly enhanced in the absence of IL-10. Thus, IL-10 may limit tissue disruption by suppressing the excessive infiltration of neutrophils and cytokine expression in a mouse model of type III vasculitis.

This Pillars of Immunology article is a commentary on “Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade,” a pivotal article written by D. L. Sylvestre and J. V. Ravetch, and published in Science, in 1994. https://www.science.org/doi/10.1126/science.8066448.

The Arthus reaction is a rare adverse reaction that usually occurs after vaccination with large and more severe local reactions, belonging to type Ⅲ hypersensitivity reaction. This reaction is characterized by pain, swelling, induration (Tissue that becomes firm) and edema, even accompanied by severe necrosis or ulceration at the injection sites. However, most of mild cases generally can be cured without treatment, and only severe cases need to be treated with anti-allergy. Therefore, this adverse reaction is often ignored by people. We searched PubMed, Web of Science and Chinese database (CNKI database and Wan Fang database) for published studies using the terms “Arthus reaction” or “Arthus phenomenon”, combined with “vaccine”, with no date or language restrictions for all publications before January 28, 2019. Only 30 cases of Arthus reaction were found, of which only one case died.4 cases of Arthus reaction post-dose-1 were reported in the review. The proportion of Arthus reaction occurred after the first, second and third injections in those case reports was 13.3%, 50.0%, and 23.3%, respectively. Arthus reaction was determined according to the clinical symptoms (The symptoms which were observed by the researchers, such as red, swelling and painful with itching at or around the injection sites). The specific causes of Arthus reaction after one dose of vaccination are not described in detail in literatures. Therefore, it could be hypothesized that the case has a pre-existing specific IgG (Such as pre-existing antibody, etc.) to cause the Arthus reaction. And 17 reported cases were observed in children younger than 6 y. In addition, we collected only 18 cases of bacterial vaccine-induced Arthus reaction and 12 cases of viral vaccines. However, there are no other data (Such as the total number and incidence rate of vaccination) in literatures, so we cannot compare statistically significant differences. At presents, no previous reviews of vaccine-induced Arthus reaction have been found. Thus, a systematic review about vaccine-associated Arthus reaction is urgently needed to deepen people‘s understanding and concern of this phenomenon. In this manuscript, we retrospectively reviewed the description of the discovery process and mechanisms of Arthus reaction, a description of the characteristics of Arthus reaction cases, reporting the Arthus reaction cases in China during 2010–2015, diagnostic criteria and general treatment, preventive measures of Arthus reaction, and challenges remaining to be investigated in the future.

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.

Repeat administration of tetanus toxoid-containing vaccines has rarely been associated with Arthus phenomenon, an immune-complex reaction. In the US, since 2013, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines (Tdap) have been recommended for administration during each pregnancy. Separately, in 2019, one Tdap was approved for repeat administration in adults in the US. We aimed to describe trends in spontaneously reported Arthus reactions following Tdap in the US and to assess the risk of this phenomenon in persons receiving Tdap repeatedly. We reviewed Arthus reports in the Vaccine Adverse Events Reporting System (VAERS), 1990–2018. Reporting rates were estimated using Tdap doses distributed data. A systematic literature review was conducted in MEDLINE for any Arthus cases reported in Tdap clinical trials and observational studies published between 2000 and 2019. We found 192 Arthus reports in VAERS after any vaccine, of which 36 occurred after Tdap and none were reported during pregnancy. The Arthus reporting rate was estimated at 0.1 per million doses distributed. We identified eight published studies of Tdap administration within five years after a previous dose of tetanus toxoid-containing vaccine; no Arthus cases were reported. We conclude that Arthus reaction following Tdap is extremely rare. Increasing frequency of repeat Tdap administration in adults in the US did not result in a detectable increase in reporting rates of this phenomenon, confirming the favorable safety profile of Tdap.

International audience; In recent years, accumulating evidence has indicated that platelets continuously repair vascular damage at sites of inflammation and/or infection. Studies in mouse models of inflammation have highlighted the fact that the mechanisms underlying bleeding prevention by platelets in inflamed organs can substantially differ from those supporting primary hemostasis following tail tip transection or thrombus formation in models of thrombosis. As a consequence, exploration of the hemostatic function of platelets in inflammation, as well as assessment of the risk of inflammation-induced bleeding associated with a platelet deficit and/or the use of anti-thrombotic drugs, require the use of dedicated experimental models. In the present review, we present the pros and cons of the cutaneous reversed passive Arthus reaction, a model of inflammation which has been instrumental in studying how inflammation causes vascular injury and how platelets continuously intervene to repair it. The limitations and common issues encountered when working with mouse models of inflammation for investigating platelet functions in inflammation are also discussed.

Objective Immune complex (IC) deposition activates polymorphonuclear neutrophils (PMNs), increases vascular permeability, and leads to organ damage in systemic lupus erythematosus and rheumatoid arthritis. The bioactive lipid sphingosine 1-phosphate (S1P), acting via S1P receptor 1 (S1P1 ), is a key regulator of endothelial cell (EC) barrier function. This study was undertaken to investigate whether augmenting EC integrity via S1P1 signaling attenuates inflammatory injury mediated by ICs. Methods In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVECs) by electrical cell-substrate impedance sensing. Phosphorylation of myosin light chain 2 (p-MLC-2) and VE-cadherin staining in HUVECs were assessed by immunofluorescence. A reverse Arthus reaction (RAR) was induced in the skin and lungs of mice with S1P1 deleted from ECs (S1P1 EC-knockout [ECKO] mice) and mice treated with S1P1 agonists and antagonists. Results S1P1 agonists prevented loss of barrier function in HUVECs treated with IC-activated PMNs. S1P1 ECKO and wild-type (WT) mice treated with S1P1 antagonists had amplified RAR, whereas specific S1P1 agonists attenuated skin and lung RAR in WT mice. ApoM-Fc, a novel S1P chaperone, mitigated EC cell barrier dysfunction induced by activated PMNs in vitro and attenuated lung RAR. Expression levels of p-MLC-2 and disruption of VE-cadherin, each representing manifestations of cell contraction and destabilization of adherens junctions, respectively, that were induced by activated PMNs, were markedly reduced by treatment with S1P1 agonists and ApoM-Fc. Conclusion Our findings indicate that S1P1 signaling in ECs modulates vascular responses to IC deposition. S1P1 agonists and ApoM-Fc enhance the EC barrier, limit leukocyte escape from capillaries, and provide protection against inflammatory injury. The S1P/S1P1 axis is a newly identified target to attenuate tissue responses to IC deposition and mitigate end-organ damage.

Platelets regulate inflammation as well as hemostasis. Inflammatory insults often induce hemostatic function through mechanisms that are not always understood. The triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is an abundantly expressed platelet receptor and its deletion leads to hemorrhage and edema after lipopolysaccharide and TNF-α treatment. To define a role for TLT-1 in immune derived bleeding we used a CXCL-2 mediated local inflammatory reaction in the vessels of the cremaster muscle of treml1 -/- and wild type mice. Our whole mount immunofluorescent staining of the cremaster muscle demonstrated a 50% reduction in clot size and increased extravasation of plasma molecules in treml1 -/- mice compared to wild type. We demonstrate that the decreased clotting in treml1 -/- mice is associated with a 2X reduction in integrin β3 phosphorylation on residue Y773 after platelet activation, which is consistent with treml1 -/- mice displaying reduced outside-in signaling and smaller thrombi. We further substantiate TLT-1's role in the regulation of immune derived bleeding using the reverse arthus reaction and demonstrate TLT-1's role in thrombosis using the thromboplastin initiated and collagen/epinephrine models of pulmonary embolism. Thus, the data presented here demonstrate that TLT-1 regulates early clot formation though the stabilization of αIIbβ3 outside-in signaling.

Chikungunya virus (CHIKV) was first isolated in humans in 1952, following an epidemic in Tanzania. The origin of the name means "to bend forward or become contorted," in reference to the posture adopted by patients due to the joint pain that occurs during the infection. Epidemiology data suggest that by the end of 2015, about 1.6 million people had been infected with CHIKV. The acute period of the disease is characterized by high fever, myalgia, joint pain, and severe and disabling polyarthritis, sometimes accompanied by headache, backache, and maculopapular rash, predominantly on the thorax. Around half of the patients will progress to the subacute and chronic phases, that is manifested by persistent polyarthritis/polyarthralgia, accompanied by morning stiffness and fatigue, which could remain for years. Oral features may include gingivitis possibly as a consequence of arthralgia of the hands leading to limited oral health measures as well as burning sensation and oral mucosal ulceration. Treatment in the acute phase includes acetaminophen, and weak opioids (tramadol or codeine) should be used in cases of severe or refractory pain. For patients who have progressed to the subacute stage and who have not had notable benefit from common analgesics or opioids, NSAIDs, or adjunctive pain medications (anticonvulsants or antidepressants) may be of benefit. In patients with moderate-to-severe musculoskeletal pain or in those who cannot be given or tolerate NSIADs or opiates, prednisolone should be prescribed.