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Heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT) are highly prothrombotic (thrombosis frequency ≥50%). Both are caused by platelet-activating anti-platelet factor 4 (PF4) antibodies, forming PF4/IgG-containing immune complexes that engage platelet FcγIIa receptors, producing strong platelet activation. In HIT, heparin crosslinks several PF4 molecules, whereas in VITT, anti-PF4 antibodies alone crosslink PF4. Sufficient levels of circulating anti-PF4 antibodies are needed to create the pathogenic immune complexes on platelet surfaces; this explains why certain serum (plasma)-based assays are highly sensitive for detecting HIT/VITT antibodies. Accordingly, HIT and VITT are "clinical-pathological" disorders, that is, positive testing for such antibodies-together with a compatible clinical picture-is integral for diagnosis. Heparin (low concentrations) enhances HIT antibody-induced platelet activation, but platelet activation by VITT sera is usually inhibited by heparin. For both HIT and VITT, high sensitivity (>99% and >95%, respectively) characterizes PF4-dependent enzyme immunoassays (EIAs) and PF4-enhanced platelet activation assays; in contrast, certain rapid immunoassays have high sensitivity for HIT (>90-97%) but poor sensitivity (<25%) for VITT. HIT and VITT antibodies are directed at distinct sites on PF4: solid-phase EIAs and platelet activation assays are indifferent to these distinct antigen targets, but rapid immunoassays are not. We discuss a conceptual model where PF4 is viewed as a "globe," with the heparin-binding site the "equator"; in this model, HIT antibodies are primarily directed at antigen site(s) at the north and south "poles" of PF4 (formed when PF4 binds to heparin), whereas VITT antibodies recognize sites on the equator., Competing Interests: T.E.W. has received lecture honoraria from Alexion and Werfen (Instrumentation Laboratory), and royalties from Informa (Taylor & Francis); has provided consulting services to Aspen Canada, Aspen Global, CSL Behring, Ergomed, Paradigm Pharmaceuticals, Octapharma, and Veralox Therapeutics; has received research funding from Werfen (Instrumentation Laboratory); and has provided expert witness testimony relating to heparin-induced thrombocytopenia (HIT) and non-HIT thrombocytopenic and coagulopathic disorders. A.D. reports personal fees from Aspen, grants from Ergomed, grants from Boehringer Ingelheim, personal fees from Bayer Vital, grants from Rovi, grants from Sagent, personal fees from Chromatec, personal fees from Instrumentation Laboratory, grants and personal fees from Macopharma, grants from Portola, grants from Biokit, personal fees from Sanofi-Aventis, grants from Blau Farmaceutics, grants from Prosensa/Biomarin, grants and other from DRK-BSD NSTOB, grants from DRK-BSD Baden-Württemberg/Hessen, personal fees from Roche, personal fees from GTH e.V., grants from Deutsche Forschungsgemeinschaft, grants from Robert-Koch-Institut, nonfinancial support from Veralox, grants from Dilaflor, nonfinancial support from Vakzine Projekt Management GmbH, grants from GIZ Else-Körner-Stiftung, grants from GIZ Else-Körner-Stiftung, nonfinancial support from AstraZeneca, nonfinancial support from Janssen Vaccines & Prevention B.V., personal fees from Takeda Pharma, personal fees from Falk Foundation e.V., grants from European Medicines Agency, personal fees from Mylan Germany, outside the submitted work. In addition, A.G. has a patent Screening Methods for transfusion-related acute lung injury (TRALI) with royalties paid to EP2321644, 18.05.2011., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a "phytoresolvin" to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Abdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA., Methods: In the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, mouse macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes., Results: Macrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNF-α and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by immune complexes in macrophages., Conclusions: Activation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment., (Copyright © 2023 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Clinical applications of skin testing are known to help diagnose IgE-mediated and T-cell-mediated delayed cutaneous reactions. By contrast, drug-induced immune complex-mediated vasculitis is primarily diagnosed based on medical history, clinical setting and laboratory evidence of immune-complex formation, as there are no proven methods to identify the suspect culprit. We report three cases of drug- or biologic-induced immune complex-mediated vasculitis, in which the culprit agents could be confirmed by a positive intradermal test with later reading (between 12 and 24 h after the test), with verification by immunohistochemical or immunofluorescent results. The findings of our study suggest that skin tests with a delayed reading could have a potential role in diagnosing some instances of immune complex-mediated hypersensitivity reactions., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Coronavirus disease 2019 (COVID-19) is a highly prothrombotic viral infection that primarily manifests as an acute respiratory syndrome. However, critically ill COVID-19 patients will often develop venous thromboembolism with associated increases in morbidity and mortality. The cause for this prothrombotic state is unclear but is likely related to platelet hyperactivation. In this review, we summarize the current evidence surrounding COVID-19 thrombosis and platelet hyperactivation. We highlight the fact that several studies have identified a soluble factor in COVID-19 patient plasma that is capable of altering platelet phenotype in vitro . Furthermore, this soluble factor appears to be an immune complex, which may be composed of COVID-19 Spike protein and related antibodies. We suggest that these Spike-specific immune complexes contribute to COVID-19 platelet activation and thrombosis in a manner similar to heparin-induced thrombocytopenia. Understanding this underlying pathobiology will be critical for advancement of future research and therapeutic options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jevtic and Nazy.)

Background: Abdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody-dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ-chain and Syk kinase) influences AAA formation in mice., Methods: FcγR gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and γ-chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC., Results: FcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase-perfused γKO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti-inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of FcγR-expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC-mediated cell responses, reduced inflammation, and mitigated AAA formation., Conclusion: Our findings provide insight into the role and mechanisms mediating IgG-FcγR-associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Glucocorticoid-induced leucine zipper (GILZ) mimics many of the anti-inflammatory effects of glucocorticoids, suggesting it as a point of therapeutic intervention that could bypass GC adverse effects. We previously reported that GILZ down-regulation is a feature of human SLE, and loss of GILZ permits the development of autoantibodies and lupus-like autoimmunity in mice. To further query the contribution of GILZ to protection against autoimmune inflammation, we studied the development of the lupus phenotype in Lyn-deficient (Lyn -/- ) mice in which GILZ expression was genetically ablated. In Lyn -/- mice, splenomegaly, glomerulonephritis, anti-dsDNA antibody titres and cytokine expression were exacerbated by GILZ deficiency, while other autoantibody titres and glomerular immune complex deposition were unaffected. Likewise, in patients with SLE, GILZ was inversely correlated with IL23A , and in SLE patients not taking glucocorticoids, GILZ was also inversely correlated with BAFF and IL18 . This suggests that at the onset of autoimmunity, GILZ protects against tissue injury by modulating pro-inflammatory pathways, downstream of antibodies, to regulate the cycle of inflammation in SLE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nataraja, Dankers, Flynn, Lee, Zhu, Vincent, Gearing, Ooi, Pervin, Cristofaro, Sherlock, Hasnat, Harris, Morand and Jones.)

Monoclonal based therapeutics have always been looked at as a futuristic natural way we could take care of pathogens and many diseases. However, in order to develop, establish and realize monoclonal based therapy we need to understand how the immune system contains or kill pathogens. Antibody complexes serve the means to decode this black box. We have discussed examples of antibody complexes both at biochemical and structural levels to understand and appreciate how discoveries in the field of antibody complexes have started to decoded mechanism of viral invasion and create potential vaccine targets against many pathogens. Antibody complexes have made advancement in our knowledge about the molecular interaction between antibody and antigen. It has also led to identification of potent protective monoclonal antibodies. Further use of selective combination of monoclonal antibodies have provided improved protection against deadly diseases. The administration of newly designed and improved immunogen has been used as potential vaccine. Therefore, antibody complexes are important tools to develop new vaccine targets and design an improved combination of monoclonal antibodies for passive immunization or protection with very little or no side effects.

Toll‑like receptors (TLRs) serve a vital role in activating the innate immune system by sensing conserved microbial products. Fc γ receptor IIb (FcγRIIb), the inhibitory Fc receptor, exerts its immune regulatory functions by binding to the immunoglobulin G Fc domain. Although the individual roles of TLRs and FcγRIIb have been studied intensively, the cross‑talk between FcγRIIb and TLR4 on B cells remains unknown. The present study demonstrated that FcγRIIb ligation by the immune complex (IC) attenuated the TLR4‑triggered nuclear factor (NF)‑κΒ activation, and decreased the release of interleukin (IL)‑6 from B cells, via enhancing LYN proto‑oncogene (Lyn) phosphorylation. In addition, IC treatment protected mice from lethal endotoxic shock. Accordingly, IC decreased the LPS‑induced serum levels of IL‑6, as well as intracellular IL‑6 production in B cells in vivo. However, these protective and inhibitory effects of IC were not observed in FcγRIIb‑/‑ mice. In conclusion, the present data demonstrated that FcγRIIb inhibited TLR4 signaling in B cells by activating Lyn phosphorylation and by inhibiting NF‑κΒ signaling. The present study elucidated the mechanism associated with the TLR4 and FcγRIIb cross‑talk in B cells.

Immune complexes (IC) used as vaccines have the potential to enhance both antibody and cell-mediated immune responses over those obtained with antigen alone. However, difficulty of manufacture represents a significant hurdle to the widespread use of IC as vaccines. Recombinant IC (RIC) and their expression in plants enable manufacturing by the coordinate expression of immunoglobulin and antigen as a fusion protein. The use of a modular RIC system facilitates insertion of antigen genes and provides a broadly applicable platform that can be adapted for a wide variety of antigens.

Interleukin-2 (IL-2) is a cytokine centrally involved in the regulation of immune tolerance and activation by its effects on CD4+ T regulatory (Treg) cells and cytotoxic effector lymphocytes, respectively. Due to these properties IL-2 immunotherapy has been used, as low-dose IL-2, in the treatment of autoimmune and chronic-inflammatory disorders; conversely, at high doses, IL-2 has shown efficacy in a subset of patients with metastatic cancer. Recent advances have highlighted the possibility of using improved IL-2-based therapies, such IL-2-antibody complexes (IL-2 complexes), able to selectively and potently stimulate either Treg cells or cytotoxic effector cells. This article discusses the properties and clinical implications of IL-2 and IL-2 complexes.

Intravenous immune globulin (IVIG) was developed initially as an immunoglobulin replacement therapy for primary humoral immunodeficiency, but is now widely used in the treatment of autoinflammatory and autoimmune pathologies. In a small number of patients, hemolytic sequelae have been observed after IVIG administration. The lack of a simple one-to-one correlation between measurable hemagglutinins and hemolysis has led to complicated hypotheses involving coincident necessary variables (e.g., a two-hit hypothesis) and also to the positing of causal factors other than hemagglutinins. One such hypothesis is that immune complexes (ICs) contained within IVIG lead to hemolysis. IVIG-mediated hemolysis was addressed at a recent meeting sponsored by the Food and Drug Administration; the Plasma Protein Therapeutics Association; and the National Heart, Lung, and Blood Institute. The primary literature was reviewed at this meeting followed by detailed discussion. Participants concluded that there is both a theoretical basis by which ICs could contribute to hemolysis after IVIG administration and some published data in support of such a possibility. However, the reported data contain substantial caveats, and the existing evidence does not rise to a level sufficient to either confirm or reject a role for ICs. More detailed and focused human studies will be required to further assess the potential role of ICs in IVIG induced hemolysis. This paper summarizes the relevant literature and expands upon the conclusions of this workshop., (© 2015 AABB.)

The neonatal Fc receptor (FcRn) is a major regulator of IgG and albumin homeostasis systemically and in the kidneys. We investigated the role of FcRn in the development of immune complex-mediated glomerular disease in mice. C57Bl/6 mice immunized with the noncollagenous domain of the α3 chain of type IV collagen (α3NC1) developed albuminuria associated with granular capillary loop deposition of exogenous antigen, mouse IgG, C3 and C5b-9, and podocyte injury. High-resolution imaging showed abundant IgG deposition in the expanded glomerular basement membrane, especially in regions corresponding to subepithelial electron dense deposits. FcRn-null and -humanized mice immunized with α3NC1 developed no albuminuria and had lower levels of serum IgG anti-α3NC1 antibodies and reduced glomerular deposition of IgG, antigen, and complement. Our results show that FcRn promotes the formation of subepithelial immune complexes and subsequent glomerular pathology leading to proteinuria, potentially by maintaining higher serum levels of pathogenic IgG antibodies. Therefore, reducing pathogenic IgG levels by pharmacologic inhibition of FcRn may provide a novel approach for the treatment of immune complex-mediated glomerular diseases. As proof of concept, we showed that a peptide inhibiting the interaction between human FcRn and human IgG accelerated the degradation of human IgG anti-α3NC1 autoantibodies injected into FCRN-humanized mice as effectively as genetic ablation of FcRn, thus preventing the glomerular deposition of immune complexes containing human IgG., (Copyright © 2014 by the American Society of Nephrology.)

Cgnz1 and Agnz1 on the distal region of mouse chromosome 1 are associated with chronic glomerulonephritis (cGN) and acute GN (aGN). NZM2328.Lc1R27 (R27) was generated by introgressing a C57L/J region where Cgnz1 is located to NZM2328. R27 female mice developed aGN mediated by immune complex (IC) deposition and complement activation without progression to cGN with severe proteinuria. End stage renal disease (ESRD) was not seen in R27 mice as old as 15 mo. Thus, aGN and cGN are under separate genetic control, and IC-mediated proliferative GN need not progress to cGN and ESRD. NZM2328 and R27 female mice have comparable immune and inflammatory parameters. In contrast to NZM2328, R27 mice were resistant to sheep anti-mouse GBM serum-induced nephritis, supporting the hypothesis that aGN is mediated by autoimmunity and resistance to the development of cGN is mediated by end organ resistance to damage. Thus, autoimmunity should be considered distinct from end organ damage. The Cgnz1 region has been mapped to a 1.34 MB region with 45 genes. Nine candidate genes were identified. Clinical relevance of these observations is supported by case studies. Clinical implications and the significance to human lupus and other diseases are presented.

C/EBPs, particularly C/EBPβ and C/EBPδ, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPβ and C/EBPδ in acute lung inflammation and injury. In this study, we show that both C/EBPβ and C/EBPδ activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPβ gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), total number of WBCs, and neutrophils in bronchoalveolar lavage fluids compared with wild-type mice. Moreover, the mutant mice expressed considerably less TNF-α, IL-6, and CXC/CC chemokine and soluble ICAM-1 proteins in bronchoalveolar lavage fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared with wild-type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPδ deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPβ-deficient alveolar macrophages released significantly less TNF-α, IL-6, MIP-2, keratinocyte cell-derived chemokine, and MIP-1α compared with wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following small interfering RNA ablation of C/EBPβ in a murine alveolar macrophage cell line. These findings implicate C/EBPβ as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung.

Allergen-specific IgE has long been regarded as a major molecular component of allergic asthma. Although IgE plays a central role in the early asthmatic response, its roles in the chronic phase, such as the late asthmatic response, airway hyperresponsiveness (AHR), and airway remodeling (goblet cell hyperplasia and subepithelial fibrosis) have not yet been defined well. In this study, we investigated the hypothesis that chronic responses could be induced by IgE-dependent mechanisms. BALB/c mice passively sensitized with an ovalbumin (OVA)-specific IgE monoclonal antibody (mAb) were repeatedly challenged with intratracheal administration of OVA. The first challenge induced early phase airway narrowing without any late response, but the fourth challenge caused not only an early but also a late phase response, AHR, and goblet cell hyperplasia. Macrophages, lymphocytes and neutrophils, but not eosinophils, were significantly increased in the lung 24h after the fourth challenge. Interestingly, levels of OVA-specific IgG1 in serum increased by multiple antigen challenges. A C3a receptor antagonist inhibited the late asthmatic response, AHR, and infiltration by neutrophils. In contrast, no late response, goblet cell hyperplasia, inflammatory cells, or production of IgG1 was observed in severe combined immunodeficient mice. On the other hand, seven challenges in BALB/c mice induced subepithelial fibrosis associated with infiltration by eosinophils. In conclusion, the allergic asthmatic responses induced by passive sensitization with IgE mAb can provide a useful model system to study the pathological roles of IgE in acute and chronic phases of allergic asthma., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale.

Background: Treatment with Bevacizumab has been associated with arterial thromboembolism in colorectal cancer patients. However, the mechanism of this remains poorly understood, and preclinical testing in mice failed to predict thrombosis., Objective: We investigated whether thrombosis might be the result of platelet activation mediated via the FcgammaRIIa (IgG) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev-induced FcgammaRIIa activation., Methods and Results: We found that Bev immune complexes (IC) activate platelets via FcgammaRIIa, and therefore attempted to reproduce this finding in vivo using FcgammaRIIa (hFcR) transgenic mice. Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin. This activity required the heparin-binding domain of Bev's target, vascular endothelial growth factor (VEGF). Heparin promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin-induced thrombocytopenia. When sub-active amounts of ADP or thrombin were used to prime platelets (simulating hypercoagulability in patients), Bev IC-induced dense granule release was significantly potentiated, and much lower (sub-therapeutic) heparin concentrations were sufficient for Bev IC-induced platelet aggregation., Conclusions: The prevailing rationale for thrombosis in Bev therapy is that VEGF blockade leads to vascular inflammation and clotting. However, we conclude that Bev can induce platelet aggregation, degranulation and thrombosis through complex formation with VEGF and activation of the platelet FcgammaRIIa receptor, and that this provides a better explanation for the thrombotic events observed in vivo.

Objective: To explore the effects of nuclear factor kappa B (NF-kappaB) in rabbit immune-complex-induced acute lung injury(ALI)., Methods: Thirty rabbits were randomly divided into 5 groups, including N, M2h, M4h, M6h and M8h groups. N group was the normal control group. M2h, M4h, M6h and M8h groups were ALI model groups. The rabbits in the N group were treated with intra-tracheal injection of 1 ml normal saline and another dose of normal saline (2 ml/kg) injected via the marginal ear vein. The rabbits in the model groups were injected intra-trachea with bovine serum albumin antibody (anti-BSA)1 ml and injected with bovine serum albumin(BSA) via marginal ear vein at dose of 2 ml/kg. Then the rabbits in the N group were killed at 8 h. The rabbits in M2h, M4h, M6h and M8h groups were killed at 2 h, 4 h, 6 h and 8 h respectively. The maleic dialdehyde (MDA) concentrations, the superoxide dismutase (SOD) activity, the protein concentrations in bronchoalveolar lavage fluid (BALF) and lung wet/dry weight ratio (W/D) were measured. The cellular distribution of NF-kappaB P65 in lung tissues was determined by immunohistochemistry., Results: The concentrations of MDA, protein in BALF and W/D of lung tissue in M2h, M4h, M6h, M8h groups increased significantly as compared with those in the N group. On the contrary, the activity of SOD in BALF in the model groups decreased significantly as compared with that of the N group. Increased expression of NF-kappaB in inflammatory cells was found in lung tissues from the model groups. The number of positive cells in M2h, M4h, M6h, M8h groups [(26.5 +/- 5.9), (39.9 +/- 6.9), (51.0 +/- 6.3), (58.0 +/- 5.3)] increased significantly as compared with that in the N group [(7.4 +/- 1.9), (t = 8.73 - 25.33, P < 0.01)]., Conclusions: Immune-complex-induced ALI animal models can be established by intra-tracheal injection of anti-BSA serum and venous injection of BSA. NF-kappaB may play an important role in immune-complex-induced ALI by inflammatory mechanism.

Compelling evidence points to a role for IgA receptors in the pathogenesis of IgA nephropathy. The soluble form of the type I IgA receptor (FcalphaRI or CD89) forms complexes with IgA that can be found in patients' serum and that initiate the disease in CD89 transgenic mice. A nonclassic IgA receptor, identified as the transferrin receptor (TfR), is highly expressed in patients' mesangium and colocalizes with IgA deposits. TfR preferentially binds polymeric IgA1 complexes, but not monomeric IgA1 or IgA2. The TfR-IgA1 interaction is dependent on carbohydrate moieties because hypoglycosylated IgA1 has superior binding to TfR than normally glycosylated IgA1. Polymeric IgA1 binding enhances mesangial cell TfR expression and results in cell proliferation and inflammatory and profibrogenic cytokine and chemokine production, suggesting a pivotal role in mesangial cell proliferation, matrix expansion, and recruitment of inflammatory cells. We propose that, as a second event, activation of the classic, FcRgamma-associated transmembrane FcalphaRI expressed on circulating myeloid leukocytes takes place. FcalphaRI/gamma2 cross-linking in human FcalphaRI transgenic animals promotes disease progression by enhancing leukocyte chemotaxis and cytokine production, and IgA immune complexes from IgA nephropathy patients induce FcalphaRI-dependent cell activation. This review therefore details the functional consequences of IgA/receptor interactions and discusses proposed mechanisms to explain the development and chronicity of the disease.

Circulating immune complexes containing aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). A portion of IgA1 secreted by IgA1-producing cells in patients with IgAN is galactose-deficient and consequently recognized by anti-glycan IgG or IgA1 antibodies. Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and mechanisms of biosynthesis have provided new insight into the autoimmune nature of the pathogenesis of this common renal disease. An imbalance in the activities of the pertinent glycosyltransferases in the IgA1-producing cells favors production of molecules with galactose-deficient O-linked glycans at specific sites in the hinge region of the alpha heavy chains. By using sophisticated analytic methods, it may be possible to define biomarkers for diagnostic purposes and identify new therapeutic targets for a future disease-specific therapy.

We have shown previously that high concentrations of IL-8 associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes) are present in lung fluids from patients with the acute respiratory distress syndrome (ARDS), and correlate both with the development and outcome of ARDS. We also detected deposition of these complexes in lung tissues from patients with ARDS but not in control tissues. Moreover, we determined that IgG receptors (FcgammaRs) mediate activity of anti-IL-8:IL-8 complexes. In the current study, we generated anti-KC (KC = chemokine (CXC motif) ligand 1 (CXCL1)) autoantibody:KC immune complexes (KC-functional IL-8) in lungs of mice to develop a mouse model of autoimmune complex-induced lung inflammation. Both wild-type (WT) and gamma-chain-deficient mice that lack receptors for immune complexes (FcgammaRs) were studied. First, the mice were immunized with KC to induce anti-KC autoantibodies. Then, KC was administered intratracheally to generate anti-KC:KC complexes in the lung. Presence of anti-KC:KC complexes was associated with development of severe pulmonary inflammation that was, however, dramatically suppressed in gamma-chain-deficient mice. Second, because sepsis is considered the major risk factor for development of ARDS, we evaluated LPS-treated WT as well as gamma-chain-deficient mice for the presence of anti-KC:KC complexes and pulmonary inflammatory responses. We detected complexes between anti-KC autoantibodies and KC in lung lavages and tissues of mice treated with LPS. Moreover, gamma-chain-deficient mice that lack receptors for immune complexes were protected from LPS-induced pulmonary inflammation. Our results suggest that immune complexes containing autoantibodies contribute to development of lung inflammation in LPS-treated mice.

A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids with hydrophobic side chains is presented. Systematic optimization of the first hits led to JPE1375 (36), which was intensively characterized in vitro and in vivo. Compound 36 exhibits high microsomal stability and receptor specificity and is highly active in an immune complex mediated peritonitis model (reverse passive Arthus reaction) in mice.

Complement proteins play an integral role in both innate and adaptive immune responses of the host. Complement activation leads to the formation of bioactive molecules including the anaphylatoxins, C3a and C5a, and the lytic membrane attack complex (C5b-9). These molecules trigger a series of events that culminate in the recruitment of phagocytic cells, release of cytokines/chemokines and reactive oxygen species, enhanced expression of adhesion molecules and apoptosis at the site of inflammation. Several animal models provide evidence that this series of events forms the basis for the pathophysiology found in many lung diseases, such as asthma and acute respiratory distress syndrome. Clinical data further confirm these findings. This review briefly discusses recent data from such studies.

The predominance of renal involvement in autoimmune diseases can most likely be assigned to the specialised function of the kidneys filtrating over 120 ml plasma per minute. Complement activation by autoantibodies directed against planted antigens or antigens already present in renal tissue in the subendothelial and mesangial regions provoke an inflammatory response ultimately resulting in renal damage. New data also suggest complement involvement in the pathogenesis of renal disease caused by subepithelial immune complex deposition. On the other hand complement itself can also be a target of an autoimmune responses causing renal damage as seen in SLE. The results on intervention of complement activation in clinical practise are awaited.

Antigen-antibody complexes can damage tissues by triggering inflammation. Recent studies have enabled the description of a sequence of steps, which depend on the intra- or perivascular location of complex formation. Acute lethal toxicity and circulatory shock as a result of the acute release of inflammatory mediators can occur after intravascular complex formation. The lesions associated with perivascular complexes are characterized by plasma leakage and the recruitment of polymorphonuclear leukocytes. These lesions are modulated by mediators released from endothelial cells, namely nitric oxide, endothelins and lipid mediators, and provide an appropriate basis for the activation of both arms of hemostasis: coagulation and fibrinolysis. The balance between both activation systems can explain the late occurrence of both tissue fibrosis and organ remodeling.

Antigen-antibody complexes can be formed both intravascularly and perivascularly and damage tissues by inducing inflammatory mechanisms. Recent studies have characterized a definite sequence of steps involved in these inflammatory mechanisms, and identified the predominance of particular chemical mediator(s) in each step. The lesions associated with this type of inflammation are characterized by the early development of plasma leakage, followed by the recruitment of polymorphonuclear leukocytes mediated by chemokines generated by FcgammaR-dependent mechanisms. The development of these lesions is modulated by endothelial cell-derived paracrine mediators, and activation of the coagulation system can ensue. The activation of platelets and coagulation, if not properly counterbalanced by fibrinolysis, might be a major factor for the late development of fibrotic changes and organ remodeling.

Background and Objectives: A patient transfused with two pooled platelet concentrates became breathless. Bilateral infiltrates were seen on chest X-ray. A diagnosis of transfusion-related acute lung injury (TRALI) was made. The patient received 100% oxygen and recovered after 5 days., Materials and Methods: Antibody screening, cross-matching for granulocyte and lymphocyte antibodies and typing for granulocyte antigens was undertaken., Results: The patient typed as HNA-1b/HNA-1b. Granulocyte and lymphocyte antibodies were not detected in the patient's serum or in any of the donor sera by cross-match. In antibody screening against typed panel granulocytes, complement-fixing anti-HNA-1a IgM antibodies were detected in the serum of one female donor. Two of the other donors who contributed to the pooled platelet concentrate containing the HNA-1a IgM antibodies typed as HNA-1a/HNA-1b., Conclusion: Anti-HNA-1a IgM antibodies may have formed immune complexes with white cell fragments or soluble FcgammaRIII from HNA-1a+ donors in the pooled platelet concentrate and initiated TRALI., (Copyright 2000 S. Karger AG, Basel)

Delayed erythropoiesis and pure red cell aplasia (PRCA) have been reported after major ABO-incompatible BMT. We attempted to find risk factors for the development of PRCA in 27 patients who underwent major ABO-incompatible BMT. In all patients, the donor marrow was depleted of RBCs before infusion. In 22 patients, isoagglutinins were determined until they disappeared. In eight (29.6%) out of 27 patients, bone marrow examination following BMT showed the findings of PRCA. We analyzed various clinico-pathologic risk factors and isoagglutinin type was the only significant risk factor. Patients with anti-A isoagglutinins against donor RBC developed PRCA more frequently than patients with anti-B (8/17 vs 0/9). Median days to the disappearance of isoagglutinins tended to be longer in patients with PRCA (PRCA vsnon-PRCA, 200 vs 66 days) and in cases with anti-A isoagglutinins (anti-A vsanti-B, 160 vs 51 days). Times to disappearance of isoagglutinins correlated with times to reticulocytes over 1% and initial appearance of donor type RBC (R2 = 0.708 and 0.711). In conclusion, RBC engraftment following major ABO-incompatible BMT was dependent on the disappearance of isoagglutinins against donor RBC, and anti-A isoagglutinin was a risk factor for the development of PRCA after major ABO-incompatible allogeneic BMT. Bone Marrow Transplantation (2000) 25, 179-184.

The classical immune complex-mediated disease, termed serum sickness, developed a short time after the injection of horse anti-tetanus toxin. Antibodies against circulating horse plasma proteins lead to the formation of immune complexes within the blood circulation (CIC). The inflammatory response, including systemic complement activation and vasculitis, seriously affected the function of all organs, including the most susceptible kidney. Meanwhile CIC have been detected in almost every systemic disease, including autoimmune disorders and also cancer and infections. This brief review will focus on the rationale and the equipment for extracorporeal elimination of CIC., (Copyright 2000 S. Karger AG, Basel)

The role of immune complexes in the etiology and pathogenesis of demyelinating diseases, particularly multiple sclerosis, is discussed in the light of numerous observations. It is inferred that a deeper understanding of the role of immune complexes might provide a basis for preventive measures in multiple sclerosis.

Immune complex formation has long been thought to play a role in the pathogenesis of Pasteurella haemolytica pneumonia. This study in laboratory rabbits was designed to investigate immune-mediated damage in respiratory tissue caused by lipopolysaccharide (LPS). Severe lesions were induced by the intratracheal (IT) injection of P. haemolytica A1 LPS (50 micrograms) into rabbits previously immunized with P. haemolytica killed whole cells emulsified with Freund's incomplete adjuvant (FIA); these lesions included perivascular oedema and polymorphonuclear leucocyte (PMN) infiltration of the subintima, with degeneration and necrosis of the media. Smaller vessels were occluded by PMNs in various stages of degranulation. PMN counts in bronchoalveolar lavage (BAL) fluid were significantly elevated (P < 0.05). Lesions were also induced by the IT injection of LPS (50 micrograms) into rabbits pretreated with an emulsion consisting merely of FIA and formol-saline; these lesions included moderate to severe congestion, interstitial oedema, alveolar serofibrinous exudation and PMN infiltration. PMNs were also present in BAL fluid. Rabbits pretreated with FIA in formol-saline and given a later IT injection of saline, and rabbits pretreated with bovine serum albumin (BSA) in FIA and given a later IT injection of BSA, were included as negative and positive control groups. Cutaneous lesions were also induced by the intradermal injection of LPS into rabbits immunized against P. haemolytica and of BSA into rabbits immunized with BSA. Overall, the pulmonary and cutaneous lesions induced in vaccinated rabbits by antigen administration were more severe than those seen in non-vaccinated rabbits. The lesions in rabbits, which were similar to those seen in natural cases of P. haemolytica pneumonia in cattle, were characterized by a fibrinopurulent inflammatory process with extensive interstitial oedema, fibrinous exudate, and PMNs. This model may help to elucidate the pathogenesis of pneumonic pasteurellosis in immunized animals.

Background and Objectives: Sodium diclofenac is one of the most widely used nonsteroidal anti-inflammatory drugs. Cases of acute haemolytic anaemia have been ascribed to the drug. We describe such a case, mediated by immune complexes., Materials and Methods: Standard serologic tests were carried out for blood grouping and the detection and identification of red cell allo- and autoantibodies. Drug-anti-drug complexes were detected with an ex-vivo method., Results: Warm IgG drug-independent red cell and platelet autoantibodies were detected in the serum. At first, the patient was diagnosed as having the Evans syndrome, and corticosteroids were administered. Later, because of the severity of the anaemia, the possibility of an immune complex mechanism was considered. This was confirmed by the detection of diclofenac-dependent antibodies that reacted with RBC only in the presence of urine from a volunteer receiving diclofenac as a source of ex-vivo antigen. The antibodies neither reacted with an in-vitro solution of the drug nor with the volunteer's serum. Diclofenac and corticosteroids were stopped, and the clinical condition of the patient completely normalised within 15 days., Conclusions: We describe a patient with acute haemolytic anaemia caused by diclofenac through an immune complex mechanism.

The typical reverse passive Arthus reaction (RPA) was attained in rats by the instillation of a rabbit antiovalbumin serum into the lungs and intravenous injection of ovalbumin. Instillation of antiserum alone caused accumulation of polymorphonuclear leukocytes (PMN) and increased vascular permeability, but did not cause hemorrhage. However, when an intravenous injection of ovalbumin was also given, the vascular permeability of the lungs increased dramatically and PMN, as well as hemoglobin, were measurable in the lung lavage fluids by 4 hr after initiation of the reaction. Various proteinase inhibitors were instilled into the lungs after the initial stages of the RPA had developed, specifically to investigate their effect on the development of the hemorrhage, which we chose to monitor as an indicator of severe vascular damage. A cephalosporin-based beta-lactam, L-658,758, which is a time-dependent inhibitor of human and rat PMN elastase, effectively prevented the lung hemorrhage associated with the RPA reaction (ED50 = 2 x 55 micrograms doses/animal when instilled at 1.5 and 2.5 hr after initiating the RPA). The PMN elastase inhibitor, methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone, also inhibited hemorrhage in this model. Compounds of the same chemical class as these elastase inhibitors, but having no activity against PMN elastase in vitro, did not affect the hemorrhage associated with the RPA. Several specific inhibitors of proteinases other than PMN elastase (e.g., pepstatin and methoxysuccinyl-prolyl-glycyl-alanyl-lysine-chloromethylketone) were found to have little effect on the hemorrhage associated with the RPA reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphological changes of blood vessel walls including various kinds of capillaries have been induced by administration of soluble immune complexes. After repeated administrations, those experimental animals who survived the phase of initial anaphylactic shock developed osteomyelitis. In this paper, the formative processes of osteomyelitis will be discussed in relation to Aschoff's definition of inflammation. We will emphasize the importance of the capillarization of the sinusoidal endothelia for the formation of osteomyelitis.

Among the many types of adverse effects of drugs, allergic reactions constitute a very significant minority, with respect to both their frequency and sometimes serious consequences. To keep the term "drug allergy" meaningful, it should be limited to those adverse drug reactions that are based on immune mechanisms or that can reasonably be presumed to have this basis. Pseudoallergic drug reactions, which will also be considered in this issue, have similar clinical manifestations and some common pathogenetic mechanisms, but the initiating event does not appear to involve a reaction between the drug or a drug metabolite and specific antibodies. Clinically, drug allergy is commonly observed in nonatopic as well as atopic people. Innumerable drugs have been reported to produce these types of reactions, but in many instances drug metabolites may be the actual culprits. Clinical manifestations of drug allergy also are legion. Unfortunately, essentially none of these is unique or specific for drug allergy, but it is important for clinicians to think of this very treatable condition along with other diagnostic possibilities. It is convenient and helpful to classify allergic reactions to drugs according to Gell and Coombs' four main types of hypersensitivity processes, but in many instances more than one mechanism may be involved, just as immune responses to most antigens generally are complex. Type I reactions are generally immunoglobulin (Ig) E-mediated, and clinical manifestations include urticaria, angioedema, respiratory symptoms, and anaphylaxis. Pseudoallergic reactions of the latter type are called anaphylactoid.(ABSTRACT TRUNCATED AT 250 WORDS)