Immune Complex Diseases

Warren, John Robert; Ward, Peter A.

doi:10.1002/9780470015902.a0002164.pub3

Cited by 7 publications

(9 citation statements)

References 14 publications

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“…Aside from neutralizing activity, IgG antibodies that bind to virus particles or viral antigens can form immune complexes (ICs) that may have a profound impact on disease pathogenesis, especially with regard to inflammation. This is observed in some autoimmune and infectious diseases where persistent ICs drive a hyperinflammatory response that damages host tissues ( 8 ). A clear mechanism underlying modulation of inflammation by antibodies is via IgG interactions with activating and inhibitory Fc gamma receptors (FcγRs) on myeloid cells, which are central regulators of the inflammatory response.…”

mentioning

confidence: 99%

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Chakraborty

González

Sievers

et al. 2021

Preprint

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Serologic markers that predict severe COVID-19 disease trajectories could enable early medical interventions and reduce morbidity and mortality. We found that distinct features of IgG Fab and Fc domain structures were present within three days of a positive test that predicted two separate disease trajectories in a prospective cohort of patients with COVID-19. One trajectory was defined by early production of neutralizing antibodies and led to mild disease. A distinct trajectory, characterized by an initial period of mild symptoms followed by rapid progression to more severe outcomes, was predicted by the absence of early neutralizing antibody responses with concomitant production of afucosylated IgGs. Elevated frequencies of monocytes expressing the receptor for afucosylated IgGs, FcγRIIIa (CD16a), were an additional antecedent in patients with the more severe outcomes. In mechanistic studies, afucosylated immune complexes in the lung triggered an inflammatory infiltrate and cytokine production that was dependent on CD16a. Finally, in healthy subjects, mRNA SARS-CoV-2 vaccination elicited neutralizing antibodies that were enriched for Fc fucosylation and sialylation and distinct from both infection-induced trajectories. These data show the importance of combined Fab and Fc domain functions in the antiviral response, define an early antibody signature in people who progressed to more severe COVID-19 outcomes and have implications for novel therapeutic strategies targeting FcγRIIIa pathways.

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mentioning

confidence: 99%

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Chakraborty

González

Sievers

et al. 2021

Preprint

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“…In our study, we found elevated IL-6 and TNFa levels, and these levels increased with each treatment cycle in concordance with increased humoral immune responses. Clearly, the formation of immune complexes and downstream reactions pose a safety risk 24 . We therefore implemented a prophylactic regimen consisting of pretreatment with cyclophosphamide/Cytoxan and glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

Translational Development of A Tumor Junction Opening Technology

Kim

Wang

et al. 2021

Preprint

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Our goal is to overcome treatment resistance in ovarian cancer patients, which occurs in most cases after an initial positive response to chemotherapy. A central resistance mechanism is the maintenance of desmoglein-2 (DSG2)-positive tight junctions between malignant cells, which prevents drug penetration into the tumor. We generated JO4, a recombinant protein that binds to DSG2, resulting in the transient opening of junctions in epithelial tumors. Here, we present studies on the clinical translation of JO4 in combination with PEGylated liposomal doxorubicin/Doxil® for ovarian cancer therapy. A manufacturing process for cGMP-compliant production of JO4 was developed. GLP toxicology studies using material from this process in DSG2 transgenic mice and cynomolgus macaques showed no treatment-related toxicities after intravenous injection at doses reaching 24 mg/kg. Multiple cycles of intravenous JO4 plus Doxil® (4 cycles, 4 weeks apart, simulating the treatment regimen in the clinical trial) elicited antibodies against JO4 that increased with each cycle and were accompanied by elevation of pro-inflammatory cytokines IL6 and TNF. Pretreatment with steroids and cyclophosphamide reduced the anti-JO4 antibody response and blunted cytokine release. Our data indicate acceptable safety of our new treatment approach if immune reactions are monitored and counteracted with appropriate immune suppression.

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“…Immune complex diseases, such as rheumatoid arthritis and systemic lupus erythematosus, encompass a diverse group of inflammatory conditions characterized by antigen‐antibody deposition. Typical manifestations are glomerulonephritis, synovitis, and dermal vasculitis 1 . Activation of neutrophils, resulting from the interaction with immune complexes, leads to the production of oxygen‐free radicals and the release of lysosomal enzymes, 2 which may bring about tissue inflammation and organ damage.…”

Section: Introductionmentioning

confidence: 99%

IgG‐aggregates rapidly upregulate FcgRI expression at the surface of human neutrophils in a FcgRII‐dependent fashion: A crucial role for FcgRI in the generation of reactive oxygen species

et al. 2020

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Autoimmune complexes are an important feature of several autoimmune diseases such as lupus, as they contribute to tissue damage through the activation of immune cells. Neutrophils, key players in lupus, interact with immune complexes through Fc gamma receptors (FcgR). Incubation of neutrophils with aggregated-IgGs caused degranulation and increased the surface expression of FcgRI within minutes in a concentration-dependent fashion. After 30 minutes, IgG aggregates (1 mg/mL) upregulated FcgRI by 4.95 ± 0.45-fold. FcgRI-positive neutrophils reached 67.24% ± 6.88% on HA-IgGs stimulated neutrophils, from 3.12% ± 1.62% in non-stimulated cells, ranking IgG-aggregates among the most potent known agonists. FcgRIIa, and possibly FcgRIIIa, appeared to mediate this upregulation. Also, FcgRI-dependent signaling proved necessary for reactive oxygen species (ROS) production in response to IgGaggregates. Finally, combinations of bacterial materials with aggregates dramatically boosted ROS production. This work suggests FcgRI as an essential component in the response of human neutrophils to immune complexes leading to the production of ROS, which may help explain how neutrophils contribute to tissue damage associated with immune complex-associated diseases, such as lupus.

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Immune Complex Diseases

Cited by 7 publications

References 14 publications

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

Translational Development of A Tumor Junction Opening Technology

IgG‐aggregates rapidly upregulate FcgRI expression at the surface of human neutrophils in a FcgRII‐dependent fashion: A crucial role for FcgRI in the generation of reactive oxygen species

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