The vaccines-associated Arthus reaction.

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.

[Immunological adjuvants. Determinant factors in the efficacy-toxicity ratio of the contemporary vaccines]. / Adyuvantes inmunológicos. Determinantes en el balance eficacia-toxicidad de las vacunas contemporáneas.

To achieve effective and safe vaccines for the prevention of not yet controlled or re-emergent infectious diseases, one of the more importance aspects is to have immunological adjuvants that allow inducing a protective immune response with an appropriate safety profile. Since 1926 the aluminium compounds have been used as adjuvants for human vaccines, and only in the last 10 years have some new products been registered. Although there an enormous quantity of proposed candidates, the toxicity is the main factor that has limited their introduction into the clinic. In this work the mechanism of action are updated, and the toxicity of the immunological adjuvants are revised, especially those that have obtained clinical approval or are close to getting it.

Safety review of the purified chick embryo cell rabies vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS), 1997-2005.

On October 20, 1997, the U.S. Food and Drug Administration (FDA) licensed Purified Chick Embryo Cell (PCEC, RabAvert) vaccine against rabies in humans following clinical trials demonstrating safety and efficacy. From October 1997 through December 2005, the Vaccine Adverse Event Reporting System (VAERS) received 336 reports of adverse events (AEs) following vaccination with PCEC vaccine in the U.S.; there were no death reports. Serious events, including 20 hospitalizations and 13 neurological events, were described in 24 (7%) reports. There was no pattern among the 13 neurological AEs suggesting a plausible relationship to vaccination. A total of 20 AEs, 3 serious, were classified as possible anaphylaxis. There were 312 non-serious AEs (93%). Nineteen reports (6%) described that the vaccination series was discontinued because of non-serious AEs. Most reported AEs are non-serious and consistent with pre-licensure safety data. The rabies risk must be carefully considered before vaccine discontinuation.

Pathogenesis of B-cell superantigen-induced immune complex-mediated inflammation.

Staphylococcal protein A (SpA) is representative of a new class of antigens, the B-cell superantigens (SAgs). These antigens bind to the Fab regions of immunoglobulin molecules outside their complementarity-determining regions. SpA, the best-studied B-cell SAg, reacts with the Fabs of most VH3+ immunoglobulins, which are expressed on 30 to 60% of human peripheral B cells. Therefore, B-cell SAgs like SpA have great potential to elicit inflammatory responses in vivo. We previously reported that the interaction of SpA with VH3+ immunoglobulin molecules leads to activation of the complement cascade and produces a histologic pattern of inflammation in the skin of a rabbit indicative of immune complex injury. To elucidate the cellular and molecular events contributing to this type of unconventional immune complex-mediated inflammation, we established a mouse peritoneal Arthus reaction model. Mice treated intravenously with human polyclonal immunoglobulin G (IgG), followed by intraperitoneal injection of SpA, showed neutrophil influx into the peritoneal cavity with peak numbers appearing at 8 h. This inflammatory reaction was dependent on the interaction of SpA with VH3+ IgG. Mast cells, FcgammaRIII, complement components, and tumor necrosis factor alpha play obligatory roles, and the reaction is associated with the local release of the CXC chemokines macrophage inflammatory protein 2 and KC. The data provide further compelling evidence for the induction of immune complex-mediated injury by a B-cell SAg and highlight important factors contributing to the pathogenesis of this novel type of inflammatory reaction.

The diphtheria and pertussis components of diphtheria-tetanus toxoids-pertussis vaccine should be genetically inactivated mutant toxins.

Replacement of cellular with acellular pertussis (aP) vaccines has considerably reduced the systemic reactions observed with diphtheria-tetanus toxoids-pertussis vaccine but has not eliminated the extensive swelling (sometimes involving an entire limb) observed after the fifth injection of diphtheria-tetanus toxoids-aP (DTaP) vaccine. This local reaction, which is likely an Arthus hypersensitivity reaction caused by high levels of antibodies reacting with DTaP vaccine, could discourage its use in adults, who serve as the major reservoir of pertussis for infants. That a critical level of antibodies to pertussis toxin is both essential and sufficient to prevent infection with Bordetella pertussis is derived from data from animal and clinical studies, including data showing the similarities between the immunity induced by diphtheria and pertussis toxoids. The genetically inactivated diphtheria and pertussis mutant toxins are more immunogenic and, therefore, induce comparable levels of antitoxin at lower protein levels than do the formalin-treated native toxins. Replacement of the diphtheria and aP components with these improved antigens will reduce the amount of protein in DTaP vaccine and, most likely, the incidence and severity of local reactions in teenagers and adults.

Association of endothelin with lung hemorrhage induced by immune complexes in rats.

The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.

Optimized conjugation ratios lead to allergen immunostimulatory oligodeoxynucleotide conjugates with retained immunogenicity and minimal anaphylactogenicity.

BACKGROUND: Immunotherapy has gradually fallen out of favor for the treatment of many allergic diseases because of the overall convenience, safety, and efficacy of medications. However, investigations suggest that allergen/immunostimulatory sequence oligodeoxynucleotide (ISS-ODN) conjugates (AICs) might have improved safety and efficacy compared with allergen extracts. OBJECTIVE: We determined whether changes in the ISS-ODN conjugation ratio would effect the immunogenicity and allergenicity of AIC. METHODS: Immunogenicity was determined by means of AIC vaccination of mice, followed by analysis of antigen-specific antibody and cytokine responses. The allergenicity of AIC was determined in mast cell release studies and in murine models of anaphylaxis and the Arthus reaction. RESULTS: AIC induced a stronger immune response than allergen alone or allergen mixed with ISS-ODN, but higher-level ISS-ODN conjugation reduced its immunogenicity modestly. In mast cell degranulation studies AIC was approximately 100-fold less allergenic than native allergen, with stepwise increases in the ODN conjugation ratio leading to stepwise decreases in allergenicity. In anaphylaxis studies death rates were reduced from 100% with native allergen challenge to as low as 0% with high-ratio ISS-ODN AIC challenge. Similar results were obtained in an Arthus reaction model. CONCLUSION: These investigations establish that AIC is both significantly more immunogenic and less allergenic than native allergens and the techniques used might have further utility for the standardization and optimization of AIC formulations for use in allergic patients.

Arthus reaction to lepirudin, a new recombinant hirudin, and delayed-type hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration.

The pathogenesis of allergic reactions to heparin is poorly understood. Clinically, this phenomenon is relevant because of its increasing incidence and the resulting therapeutic challenges due to various cross-reactions between unfractionated and low-molecular weight heparins as well as between heparins and heparinoids. A 44-year-old female patient had developed a delayed-type hypersensitivity to certoparin-sodium. Diagnostic allergy testing revealed various cross-reactions between different heparins as well as an intolerance to heparinoids. After subcutaneous challenge with the recombinant hirudin lepirudin (Refludan) the patient developed a local Arthus reaction at the injection site. In general, recombinant hirudins do not cross-react with high- or low-molecular weight heparins and heparinoids because of a different molecular structure and are therefore an alternative in case of adverse reactions to heparins and heparinoids. Whereas a local Arthus reaction has already been described twice for low-molecular weight heparins, this is to the best of our knowledge the first observation of a superficial leukocytoclastic vasculitis due to s.c. applied lepirudin. Intravenous administration of heparins and heparinoids in case of hypersensitivity to these drugs following topical application risks a generalized eczematous reaction in patients with delayed-type allergy to both groups of substances. In our patient with delayed-type hypersensitivity to heparins and heparinoids and superficial vasculitis due to lepirudin, the intravenous challenge with heparin and a heparinoid was justified as an ultima ratio measure and proved to be the useful therapeutical alternative.

Arthus reaction to recombinant hepatitis B virus vaccine.

A severe, local, inflammatory, late-phase reaction accompanied by skin necrosis occurred after an infant was given an intramuscular injection of recombinant hepatitis B virus vaccine. The clinical course and appearance of the rash were typical of an Arthus reaction. Although not identical to this case, prior reported cases of complement-mediated reactions occurring after hepatitis B virus infection or vaccination provide theoretical support for this diagnosis.

The potential role of the Arthus and Shwartzman reactions in the pathogenesis of pneumonic pasteurellosis.

Pneumonic pasteurellosis (PP) is an economically important disease in cattle, sheep, and goats. Pasteurella haemolytica is commonly isolated from the severe fibrinopurulent pneumonia that characterize this respiratory syndrome. During infection, the bacteria produce leukotoxin (LKT) and lipopolysaccharide (LPS), both potent inducers of inflammation. Nonetheless, it has also been demonstrated that an exacerbated host's inflammatory response is responsible for the severe lung damage. Despite research in this field, the pathogenesis of PP is still incomplete. Two classical models of acute inflammatory response induced in laboratory animals, the Arthus and Shwartzman reactions, could explain the pathogenesis of the severe lung lesions that characterize PP.

On the role of complement and Fc gamma-receptors in the Arthus reaction.

The contribution of either the complement system or the activation of Fc receptors for IgG (FcyRs) to the inflammatory response in immune complex (IC) disease is puzzling. A series of studies has been performed in mice with engineered deficiencies of either FcgammaRs, the complement components C3, C4 or the C5a receptor. In addition, different C5-deficient mice strains have been evaluated. Mice with gene targeted disruption of the gamma-subunit, which mediates surface expression and signal transduction of the high affinity Fc receptor type I for IgG (FcgammaRI), the low affinity receptor Fc receptor type III for IgG (FcgammaRIII) and the high affinity receptor type I for IgE (IgepsilonRI), showed an impaired inflammatory response in the reverse passive Arthus reaction in skin, peritoneum and lung. These data suggest, that the activation of FgammaRs is the initial event triggering the inflammatory cascade in IC disease. On the other hand, C5aR deficient mice are either protected from tissue injury induced by ICs, as in the lung, or the degree of the inflammatory response is markedly attenuated, as in peritoneum and skin. A detailed analysis of data obtained with the different knock-out strains revealed that both the activation of the complement system as well as the activation of different effector cells via FcgammaRs contribute to the inflammatory sequelae leading to tissue destruction in IC disease. The relative contributions of FcgammaRI or FcgammaRIII and the main effector cells through which these receptors mediate their effector functions are tissue dependent. The activation of the C5a receptor pathway appears to be the prominent contribution of the complement system.

Nitric oxide inhibits neutrophil infiltration in the reverse passive arthus reaction in rat skin.

The role of nitric oxide (NO) in the reverse passive Arthus reaction elicited in the rat skin has been studied. The reverse passive Arthus reaction was modulated by test compounds given by intradermal injection in combination with anti-bovine serum albumin antibody. L-arginine (1.5-15 micromol/site) and the NO donor [1-hydroxy-2-oxo-3,3-bis (3-amonoethyl)- 1-triazenel (NOC-18; 1-10 micromol/site) both significantly reduced neutrophil infiltration and increased plasma leakage. The NO scavenger haemoglobin (30 and 100 micromol/site) did not affect oedema formation but increased neutrophil infiltration and attenuated the effects of L-arginine. The non-selective nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl ester (0.3-100 nmol/site) and N(G)-monomethyl-L-arginine (0.3-100 nmol/site) or the relatively selective inhibitors of the inducible NO synthase aminoguanidine (30-1000 nmol/site) and S-methylthiourea (3-1000 nmol/site) significantly reduced plasma leakage when given at high doses. Furthermore all these inhibitors exhibited a dose-related biphasic effect on neutrophil infiltration which was significantly increased by low doses and reduced by high doses, while intermediate doses had no effect. Phenylpropanolamine, a sympathomimetic vasoconstrictor (15-60 micromol/site), dose-dependently reduced both oedema formation and neutrophil infiltration. These results provide evidence for a relevant role of NO as a modulator of rat dermal reverse passive Arthus reaction and suggest that at the vascular level NO controls primarily the interaction between leucocyte and endothelial cell rather than the vascular permeability.

In vivo inflammatory response to a prototypic B cell superantigen: elicitation of an Arthus reaction by staphylococcal protein A.

Staphylococcal protein A (SpA) is representative of a new class of Ags, the B cell superantigens (SAgs). These SAgs, unlike conventional Ags, bind to the Fab regions of Ig molecules outside their complementarity-determining regions. In addition, B cell SAgs can react with a substantial amount of a host's serum Igs by virtue of their ability to interact with many members of an entire variable heavy chain (VH) or variable light chain gene family. For example, SpA reacts with the Fabs of most human Igs using heavy chains from the VH3 gene family (VH3+). Members of this gene family are expressed on 30 to 60% of human peripheral B cells. We sought to determine whether the interaction of a B cell SAg with its reactive Igs can elicit immune complex-mediated tissue injury. Using the Arthus reaction in rabbits as an in vivo model of immune complex-mediated tissue inflammation, we demonstrated that untreated rabbits, which were administered SpA intradermally (i.d.), do not develop a cutaneous inflammatory response. However, when rabbits were pretreated i.v. with human IgG (hIgG), i.d. injections of SpA induced an inflammatory response with the classical histologic features of an Arthus reaction. To determine whether this Arthus-like response occurred via a B cell superantigenic mechanism, the rabbits were pretreated with VH3-depleted hIgG and then were administered SpA i.d. We found that the induction of a prominent inflammatory response by SpA was dependent upon the presence of VH3+ molecules in the hIgG pretreatment. These results provide compelling evidence that an interaction of the B cell SAg, SpA, with its reactive (VH3+) IgGs leads to an immune complex-mediated inflammatory response in vivo.

Development of antibodies to fetal calf serum with arthus-like reactions in human immunodeficiency virus-infected patients given syngeneic lymphocyte infusions.

In an attempt to restore immune competence to 12 human immunodeficiency virus-1 (HIV-1)-infected patients, lymphocytes from their HIV-1-uninfected identical twin siblings were cultured in medium supplemented with 5% fetal calf serum (FCS), anti-CD3 antibody, and interleukin-2 (100 IU/mL) for 10 days and then infused into the patients. After multiple infusions, at 6- to 8-week intervals, half of the patients developed arthus-like reactions within 4 to 12 hours of infusion consisting of fever > 39 degrees C, hypotension, rigors, arthralgias, myalgias, headache, and/or malaise. Preinfusion and postinfusion serum samples were evaluated for the presence of antibodies to FCS using double immunodiffusion. All preinfusion serum samples were negative by this method while 8 of the 12 patients developed antibodies to a single component of FCS after two or more infusions of lymphocytes cultured in FCS-supplemented medium. Prick skin testing to standardized beef extract was negative in all patients. There was a correlation between initial CD4 level and the development of antibodies to FCS (median initial CD4 count in FCS antibody positive patients = 362.0/microL v median initial CD4 count of nonresponders = 135.0/microL). There was no correlation with response to recall antigens in delayed-type hypersensitivity testing. We conclude that selected patients were sensitized to a single component of FCS carried on donor lymphocytes, despite thorough washing of the cells before infusion. The development of antibodies to FCS indicates that immune complex formation could have occurred after the cell infusions, resulting in the arthus-like reactions. These observations suggest that the therapeutic use of human lymphocytes cultured in FCS may expose the recipient to immunogenic substances with possible clinical sequelae.

Erythrogenic toxin-induced arteritis in a rabbit ear model. Comparison with Arthus reaction angiitis.

We have developed a local type experimental model of angiitisin rabbits. Repeated intracutaneous injections of erythrogenic toxins types A and C (ETA, ETC) along the intermediate auricular artery of the rabbit ear produced subacute type arteritis, characteristic of lymphocyticinfiltration, simulating Kawasaki disease angiitis. Staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST) also induced similar lesions, indicating superantigens as inflammogens in vivo. Conversely, the Arthus reaction included acute type angiitis when tested similarly in rabbits immunized to human serum albumin. The ear artery was infiltrated by heterophil leukocytes, often together with venules and capillaries affected, resembling periarteritis nodosa and leukoclastic vasculitis in human disease.

Role of P-selectin in the early stage of the Arthus reaction.

P-selectin is rapidly translocated to the surface of endothelial cells and platelets following exposure to chemical mediators such as histamine, thrombin and complement factors. The Arthus reaction is caused by vascular injury which is initiated by the local deposition of the immune complex followed by the activation of complement and release of chemical mediators. In this report, the role of P-selectin in the early stage of reverse passive Arthus reaction in rat using monoclonal antibodies (mAbs) against rat P-selectin will be investigated. Intravenous administration of the mAb ARP2-4 significantly attenuated paw edema 1 h after challenging it with antigen by 31.5% (1 mg/kg) and 44.7% (3 mg/kg), respectively. Edema formation was also reduced by sulfatide (73.1%, 50 mg/kg) and inositol hexakisphosphate (InsP6) (72.9%, 30 mg/kg), which have been reported to block P-selectin-mediated neutrophil adhesion. Moreover, neutrophil accumulation into the inflammatory site in the Arthus reaction was inhibited by anti-P-selectin mAb. P-selectin expression was detected along vessel walls prior to neutrophil accumulation, as determined by immunohistochemical staining using the antibody. In addition, the expression of P-selectin mRNA was induced 4 h after deposition of immune complex. From these results, we concluded that P-selectin plays an important role in the pathogenesis of the Arthus reaction especially in the early stage by recruiting neutrophils into sites of inflammation.

The role of complement, platelet-activating factor and leukotriene B4 in a reversed passive Arthus reaction.

1. The mechanisms underlying oedema formation induced in a reversed passive Arthus (RPA) reaction and, for comparison, in response to zymosan in rabbit skin were investigated. 2. Oedema formation at skin sites was quantified by the accumulation of intravenously-injected 125I-labelled human serum albumin. 3. Recombinant soluble complement receptor type 1 (sCR1), administered locally in rabbit skin, suppressed oedema formation induced in the RPA reaction and by zymosan. 4. The platelet-activating factor (PAF) antagonists, WEB 2086 and PF10040 administered locally, inhibited oedema formation induced in the RPA reaction and by PAF but not by zymosan. 5. A locally administered leukotriene B4 (LTB4) antagonist, LY-255283, inhibited oedema formation induced by LTB4 but did not inhibit oedema responses to PAF, zymosan or the RPA reaction. 6. The results demonstrate a role for complement in oedema formation in both the RPA reaction and in response to zymosan. An important contribution by PAF is indicated in the RPA reaction but not in response to zymosan whereas no evidence was obtained to suggest a role for LTB4 in either inflammatory response.

Mast cells contribute to fibrin deposition in reverse passive Arthus reaction in mouse skin.

The activation of the clotting system is an important process during inflammation to contain the injury and initiate tissue repair. In the present study, we investigated the effect of mast cells on fibrin deposition in reverse passive Arthus reaction in mast cell-deficient WBB6F1-W/Wv(W/Wv) and control WBB6F1-(+)/+(+/+) mice, that were given 125I-labeled fibrogen intravenousty. An antibody dose-dependent increase in radioactivity was observed in the challenged skin sites. Sequential water and urea extractions characterized the radioiodinated fibrinogen derivatives present in the tissue. The radioactivity found in the various fractions of the stimulated samples from +/+ was 2-10-fold higher than that in specimens from W/Wv mice. The greatest difference was observed in the urea-insoluble pellet (cross-linked fibrin and its early degradation products). Reconstitution of W/Wv mice with mast cells augmented the response to levels similar to those in +/+ mice. Pretreatment with the antihistamine pyrilamine blocked the accumulation of 125I-labeled fibrinogen and its derivatives by approximately 70% in +/+ but not in W/Wv mice. Inhibition of leukotriene synthesis by A-63162 markedly decreased the accumulation of iodinated fibrinogen in both +/+ and W/Wv mice. The data suggest that mast cells and their vasoactive mediator histamine contribute to the exudation of clotting factors, which results in fibrin deposition and that mast cells also enhance fibrin cross-linkage.

Augmentation of reverse arthus reaction by mast cells in mice.

Immune complex-induced injury is an important pathogenic factor in antibody-mediated nephritis, systemic lupus erythematosus, rheumatoid arthritis, and other diseases. In this study we investigated the role mast cells in immune complex-mediated injury in mouse skin. Reverse Arthus reaction was induced in mast cell-deficient WBB6F1-W/Wv mice and their congenic controls (WBB6F1(-)+/+). Serial skin sections were evaluated for neutrophil infiltration, edema, and hemorrhage. In WBB6F1-W/Wv mice the neutrophil influx was only 40% and edema 60% of that in congenic controls. Hemorrhage was also significantly reduced in the mast cell-deficient mice. After mast cell reconstitution, the magnitude of the reaction in WBB6F1-W/Wv was equivalent to that in WBB6F1(-)+/+ mice. Mast cell release in reverse Arthus reaction was evaluated by measuring fluorescence intensity after avidin-FITC staining of mast cell granules. There was a 70% decrease in fluorescence intensity. The 5-lipoxygenase inhibitor A-63162 significantly decreased neutrophil accumulation (40%), edema (60%), and hemorrhage in WBB6F1(-)+/+, but not in mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/Wv mice restored the effect of A-63162. The results indicate that mast cells and their mediators, including leukotrienes, make an important contribution to reverse Arthus reaction.