Common Variable Immunodeficiency and Selective IgA Deficiency: Focus on Autoimmune Manifestations and Their Pathogenesis

International Journal of Translational Medicine, Год журнала: 2023, Номер 3(4), С. 432 - 460

Опубликована: Окт. 16, 2023

Inborn errors of immunity (IEI) are multifaced diseases which can present with a variety phenotypes, ranging from infections to autoimmunity, lymphoproliferation, and neoplasms. In recent decades, research has investigated the relationship between autoimmunity IEI. Autoimmunity is more prevalent in primary humoral immunodeficiencies than most other IEI it even be their first manifestation. Among these, two common selective IgA deficiency variable immunodeficiency. More half patients these conditions develop non-infectious complications due immune dysregulation: autoimmune, autoinflammatory, allergic disorders, malignancies. Around 30% autoimmune phenomena, such as cytopenia, gastrointestinal respiratory complications, endocrine dermatologic features. Complex alterations central peripheral mechanisms tolerance involved, affecting mainly B lymphocytes but also T cells cytokines. Not only immunophenotype advances genetics allow us diagnose monogenic variants investigate pathogenetic basis dysregulation. The diagnosis therapy been mostly focused on infectious while predominant features dysregulation still challenge for clinician an opportunity therapeutic research.

Язык: Английский

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In vivo antiviral efficacy of LCTG-002, a pooled, purified human milk secretory IgA product, against SARS-CoV-2 in a murine model of COVID-19

Human Vaccines & Immunotherapeutics, Год журнала: 2024, Номер 20(1)

Опубликована: Янв. 22, 2024

Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosae, with secretory form (sIgA) being dominant and uniquely stable. sIgA challenging to produce recombinantly but naturally found milk, which could be considered a global resource for this biologic, justifying its development as mucosal therapeutic. Presently, SARS-CoV-2 was utilized model pathogen, methods were developed efficiently extract milk from donors who naïve or had recovered infection that elicited high-titer anti-SARS-CoV-2 Spike their (pooled make LCTG-002). Mass spectrometry determined proteins relative abundance of 1% greater all associated sIgA. Western blot demonstrated batches consisted predominantly Compared control IgA, LCTG-002 significantly higher binding (mean endpoint 0.87 versus 5.87). capable blocking receptor-binding domain - angiotensin-converting enzyme 2 (ACE2) interaction potency compared IC50 154ug/mL 50% inhibition not achieved control), exhibited significant neutralization activity against Spike-pseudotyped virus 49.8ug/mL 114.5ug/mL control). tested capacity reduce viral lung burden K18+hACE2 transgenic mice inoculated SARS-CoV-2. reduced titers when administered at 0.25 mg/day 1 mg/day, maximum TCID50 reduction 4.9 logs. This innovative study demonstrates highly pure efficacious vivo, supporting further milk-derived, polyclonal therapeutics.

Язык: Английский

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Combinatorially restricted computational design of protein-protein interfaces to produce IgG heterodimers

Science Advances, Год журнала: 2024, Номер 10(15)

Опубликована: Апрель 10, 2024

Redesigning protein-protein interfaces is an important tool for developing therapeutic strategies. Interfaces can be redesigned by in silico screening, which allows efficient sampling of a large protein space before experimental validation. However, computational costs limit the number combinations that reasonably sampled. Here, we present combinatorial tyrosine (Y)/serine (S) selection (combYSelect), approach combining determination change binding free energy (ΔΔ

Язык: Английский

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Conjugated Nonionic Detergent Micelles: An Efficient Purification Platform for Dimeric Human Immunoglobulin A

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(6), С. 979 - 986

Опубликована: Май 15, 2024

The SARS-COV-2 virus is a deadly agent of inflammatory respiratory disease. Since 2020, studies have focused on developing new therapies based galactose-rich IgA antibodies. Clinical surveys also revealed that galactose-deficient IgA1 polymerizes in serum, producing nephropathy, which common cause kidney failure young adults. Here we show IgA1-IgA2 dimers are efficiently and economically purified solution via conjugated nonionic surfactant micellar aggregates. Quantitative capture at pH 7 extraction 6.5 can avoid antibody exposure to acidic, potentially denaturing conditions. Brij-O20 aggregates lead the highest process yields (88-91%) purity (94%). Recovered preserve their native secondary structure do not self-associate. Increasing reaction volume has little impact yield or purity. By introducing an efficient, inexpensive purification protocol, assist pharmaceutical firms research laboratories IgA-based as well increasing our understanding polymerization.

Язык: Английский

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A Possible Protective Effect of IgA Against Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) in Bronchoalveolar Lavage in COVID-19 Patients Admitted to Intensive Care Unit

Viruses, Год журнала: 2024, Номер 16(12), С. 1851 - 1851

Опубликована: Ноя. 28, 2024

SARS-CoV-2 infection induces a humoral immune response, producing virus-specific antibodies such as IgM, IgG, and IgA. IgA are present at mucosal sites, protecting against respiratory other infections, including SARS-CoV-2, by neutralizing viruses or impeding attachment to epithelial cells. Since spreads through the nasopharynx, specific IgAs of produced quickly after infection, effectively contributing virus neutralization. Dimeric has been reported be 10 15 times more potent than its equivalent suggesting that this isotype may particularly interesting in developing new monoclonal and/or vaccines efficiently sites. It is still unclear whether BAL might play role disease course if their presence have prognostic significance. However, harmful effect on diseases with high titers reported. This study evaluated mucosal-specific IgG profiles patients COVID-19 acute failure admitted ICU. We included 57 (41 males 16 females), ICU University Foggia. used commercially available ELISA assay evaluate plasma hospitalized severe failure. 40/57 from infected were for test; remaining specimens unsuitable. detectable 37 (92.5%) 40 (100%) specimens, respectively. found single sample, while detected 19 samples analyzed. Correlations between these parameters patient outcomes reveal signature associated survival. Interestingly, statistically significant inverse correlation was mortality rate specimens. None positive died, compared 7 out 12 negative IgA-BAL (p: <0.0004). Despite being limited size, suggests protective immunity patients, even advanced stages, defense virus, well possible use effective therapeutic strategies based antibodies.

Язык: Английский

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Clonally expanded IgG antibody-secreting cells preferentially target influenza nucleoprotein following homologous and heterologous infections

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 11, 2024

Abstract Infection with influenza virus remains a significant global health concern due to its ability acquire mutations at key antigenic sites escape antibody recognition. While germinal center (GC) and memory B cells have been well studied following infection, the clonal dynamics of secreting (ASCs), particularly those within bone marrow (BM) niche that are responsible for serum immune protection, remain poorly understood. Here, we combine single-cell RNA (scRNA) cell receptor (BCR) sequencing characterize individual ASCs various Influenza exposure histories. We find BM repertories populated by highly expanded class-switched infection similar transcriptional repertoire characteristics regardless homologous or heterologous By combining analysis monoclonal expression characterization, large proportion IgG-, but not IgA-, ASC demonstrates specificity nucleoprotein (NP). Together, our data reveal complex relationship between repertoires, mucosal humoral responses, BCR antigen during infection.

Язык: Английский

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Prebiotics and vitamins enhance gut barrier in a randomized double-blind placebo-controlled trial

Nutrition & Food Science, Год журнала: 2024, Номер unknown

Опубликована: Дек. 28, 2024

Purpose Intestinal mucosa functions as a specialized permeable barrier, facilitating nutrient absorption and safeguarding against external influences. Gut barrier serves channel of communication between gastrointestinal bodily processes. Research investigations have postulated that enhancing gut through microbiota could potentially enhance overall well-being. Hence, this intervention study was designed to assess whether modulators delivers intestinal extra-intestinal benefits. Design/methodology/approach A randomized, double-blind, placebo-controlled trial devised examine the impact two doses (1.5 3 g) intervention, comprising prebiotics vitamins on indicators (faecal IgA calprotectin) markers (lactobacilli bifidobacteria) healthy human subjects. In addition, cholera vaccine challenge test conducted influence improvement mucosal response stressor. Findings After weeks resulted in significant ( p = 0.04) enhancement faecal levels compared placebo. This coincided with an increase lactobacilli bifidobacteria. < 0.001) reduction calprotectin observed both groups at end Following challenge, markedly 0.03) heightened documented groups. limitations/implications illustrated combination effectively modulate individuals, which contribute good health. These findings establish foundation for delivering optimal dwelling from gut. Originality/value is one its kind has probed into physiological health markers.

Язык: Английский

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