MicroRNA-23b-3p Deletion Induces an IgA Nephropathy-Like Disease Associated with Dysregulated Mucosal IgA Synthesis

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger glomerular inflammation. A growing body of evidence suggests that dysregulated expression of microRNAs in IgAN may play a significant role in establishing the disease phenotype. Methods: We generated single miR-23b-3p(miR-23b) knockout mice using CRISPR-Cas9. Results: In humans, miR-23b levels are downregulated in kidney biopsies and sera of patients with IgAN, and serum miR-23b levels are negatively correlated with serum IgA1 levels. We show that miR-23b-/- mice develop an IgAN-like phenotype of mesangial IgA and C3 deposition associated with development of albuminuria, hypertension, an elevated serum creatinine, and dysregulated mucosal IgA synthesis. Dysregulation of IgA production is likely mediated by the loss of miR-23b mediated suppression of activation-induced cytidine deaminase in mucosal B cells. In addition, we show that loss of miR-23b increases the susceptibility of the kidney to progressive fibrosis through loss of regulation of expression of gremlin 2 and IgA accumulation through downregulation of the transferrin receptor. Conclusions: Our findings suggest an indispensable role for miR-23b in kidney disease, and in particular, IgAN. miR-23b may in the future offer a novel therapeutic target for the treatment of IgAN.

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A Soluble Fiber Diet Increases Bacteroides fragilis Group Abundance and Immunoglobulin A Production in the Gut

Applied and Environmental Microbiology ◽

10.1128/aem.00405-20 ◽

2020 ◽

Vol 86 (13) ◽

Cited By ~ 3

Author(s):

Akihito Nakajima ◽

Takashi Sasaki ◽

Kikuji Itoh ◽

Takashi Kitahara ◽

Yoshinori Takema ◽

...

Keyword(s):

Gut Microbiota ◽

Cytidine Deaminase ◽

Immunoglobulin A ◽

Bacteroides Fragilis ◽

Content Type ◽

High Fiber ◽

Fiber Diet ◽

Bowel Diseases ◽

High Fiber Diet ◽

Iga Production

ABSTRACT Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Previous studies have shown that Bacteroidetes, the major phylum of gut microbiota together with Firmicutes, impact IgA production. However, the relative abundances of species of Bacteroidetes responsible for IgA production were not well understood. In the present study, we identified some specific Bacteroidetes species that were associated with gut IgA induction by hsp60-based profiling of species distribution among Bacteroidetes. The levels of IgA and the expression of the gene encoding activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were increased in soluble high-fiber diet (sHFD)-fed mice. We found that Bacteroides acidifaciens was the most abundant Bacteroidetes species in both sHFD- and normal diet-fed mice. In addition, the gut IgA levels were associated with the relative abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciens. Conversely, the ratio of B. acidifaciens to other Bacteroidetes species was reduced in insoluble high-fiber diet fed- and no-fiber diet-fed mice. To investigate whether B. acidifaciens increases IgA production, we generated B. acidifaciens monoassociated mice and found increased gut IgA production and AID expression. Collectively, soluble dietary fiber increases the ratio of gut Bacteroides fragilis group, such as B. acidifaciens, and IgA production. This might improve gut immune function, thereby protecting against bowel pathogens and reducing the incidence of inflammatory bowel diseases. IMPORTANCE Immunoglobulin A (IgA) is essential for defense of the intestinal mucosa against harmful pathogens. Gut microbiota impact IgA production, but the specific species responsible for IgA production remain largely elusive. Previous studies have shown that IgA and Bacteroidetes, the major phyla of gut microbiota, were increased in soluble high-fiber diet-fed mice. We show here that the levels of IgA in the gut and the expression of activation-induced cytidine deaminase (AID) in the large intestine lamina propria, which is crucial for class switch recombination from IgM to IgA, were correlated with the abundance of Bacteroides fragilis group species such as Bacteroides faecis, Bacteroides caccae, and Bacteroides acidifaciens. B. acidifaciens monoassociated mice increased gut IgA production and AID expression. Soluble dietary fiber may improve gut immune function, thereby protecting against bowel pathogens and reducing inflammatory bowel diseases.

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The Potential Role of an Aberrant Mucosal Immune Response to SARS-CoV-2 in the Pathogenesis of IgA Nephropathy

Pathogens ◽

10.3390/pathogens10070881 ◽

2021 ◽

Vol 10 (7) ◽

pp. 881

Author(s):

Zhao Zhang ◽

Guorong Zhang ◽

Meng Guo ◽

Wanyin Tao ◽

Xingzi Liu ◽

...

Keyword(s):

Immune Response ◽

Iga Nephropathy ◽

Early Stage ◽

Elevated Serum ◽

Serum Levels ◽

Mucosal Immune Response ◽

Elevated Concentration ◽

Protein Receptor ◽

Iga Production ◽

Antibody Levels

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global concern. Immunoglobin A (IgA) contributes to virus neutralization at the early stage of infection. Longitudinal studies are needed to assess whether SARS-CoV-2-specific IgA production persists for a longer time in patients recovered from severe COVID-19 and its lasting symptoms that can have disabling consequences should also be alerted to susceptible hosts. Here, we tracked the anti-SARS-CoV-2 spike protein receptor-binding domain (RBD) antibody levels in a cohort of 88 COVID-19 patients. We found that 52.3% of the patients produced more anti-SARS-CoV-2 RBD IgA than IgG or IgM, and the levels of IgA remained stable during 4–41 days of infection. One of these IgA-dominant COVID-19 patients, concurrently with IgA nephropathy (IgAN), presented with elevated serum creatinine and worse proteinuria during the infection, which continued until seven months post-infection. The serum levels of anti-SARS-CoV-2 RBD and total IgA were higher in this patient than in healthy controls. Changes in the composition of the intestinal microbiota, increased IgA highly coated bacteria, and elevated concentration of the proinflammatory cytokine IL-18 were indicative of potential involvement of intestinal dysbiosis and inflammation to the systemic IgA level and, consequently, the disease progression. Collectively, our work highlighted the potential adverse effect of the mucosal immune response to SARS-CoV-2 infection, and that additional care should be taken with COVID-19 patients presenting with chronic diseases such as IgAN.

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TACI regulates IgA production by APRIL in collaboration with HSPG

Blood ◽

10.1182/blood-2006-08-041772 ◽

2006 ◽

Vol 109 (7) ◽

pp. 2961-2967 ◽

Cited By ~ 87

Author(s):

Daisuke Sakurai ◽

Hidenori Hase ◽

Yumiko Kanno ◽

Hidefumi Kojima ◽

Ko Okumura ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Cytidine Deaminase ◽

Negative Regulator ◽

Cell Responses ◽

Activation Induced Cytidine Deaminase ◽

B Cell Responses ◽

Iga Production ◽

Necrosis Factor

Abstract Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is a member of the tumor necrosis factor (TNF) receptor family that serves as a receptor for B-cell activating factor of the TNF family (BAFF) and as a proliferation-inducing ligand (APRIL). Although TACI is reported to function as a positive or negative regulator for B-cell responses, its roles remain elusive. Experiments using TACI siRNA into B cells indicated that TACI positively regulated APRIL-induced IgA production in collaboration with heparan sulfate proteoglycans (HSPG). Furthermore, TACI negatively regulated BAFF-induced B-cell proliferation and production of IgA and IgG. In addition, B cells treated with heparitinase to denature HSPG showed that HSPG is essential for APRIL-induced B-cell responses such as B-cell proliferation, IgG and IgA production, induction of activation-induced cytidine deaminase (AID), and noncanonical NF-κB2. In contrast, phosphorylation of physiological AID kinase, protein kinase A (PKA), was dependent on TACI. Importantly, coligation of TACI and HSPG by specific antibodies, but not by TACI or HSPG ligation itself, could induce the phosphorylation of PKA and IgA production instead of APRIL. Our findings indicate that simultaneous binding of TACI and HSPG on B cells with APRIL is crucial for IgA production.

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Increased Expression of Activation-Induced Cytidine Deaminase in Sinus Mucosa from IgG4-Related Disease Patients with Comorbid Chronic Rhinosinusitis

ORL ◽

10.1159/000515797 ◽

2021 ◽

pp. 1-9

Author(s):

Tomohito Nojima ◽

Manabu Nonaka ◽

Yukako Seo ◽

Yukie Yamamura ◽

Masayoshi Mukai

Keyword(s):

Chronic Rhinosinusitis ◽

Cytidine Deaminase ◽

Elevated Serum ◽

Ethmoid Sinus ◽

Distinct Form ◽

Related Disease ◽

Igg4 Related Disease ◽

Serum Igg4 ◽

Activation Induced Cytidine Deaminase ◽

Sinus Mucosa

Objective: IgG4-related disease (IgG4-RD) is a systemic condition characterized by an elevated serum IgG4 level, localized infiltration of IgG4-positive plasma cells, and lesions in various organs. IgG4-RD also shows high rates of complication with allergic diseases and is often accompanied by elevated serum IgE levels. Reports in recent years have also shown high rates of complication with chronic rhinosinusitis (CRS) and its characteristic nasal manifestations. Accordingly, we speculate that there may be a distinct form of CRS that, as an IgG4-RD, differs from other CRS. Here, we investigated whether the elevated levels of factors that are thought to be important in the pathogenesis of IgG4-RD are also seen in the sinus mucosa of IgG4-RD-associated CRS patients. Methods: Ethmoid sinus mucosa specimens from 9 IgG4-RD (6 Mikulicz disease and 3 Küttner’s tumor) patients with elevated serum IgG4 and IgE and from 22 control CRS patients were examined immunohistochemically for Treg cytokines (IL-10 and TGF-β), activation-induced cytidine deaminase (AID), and immunocompetent cells. The 22 control CRS patients were divided into 3 subgroups based on the serological findings for IgG4 and IgE. Quantitative real-time PCR was performed to examine the expression of AID. Results: The ethmoid sinus mucosa from patients with IgG4-RD-associated CRS showed, in comparison with the 3 CRS control subgroups, significantly elevated AID production. Their mucosa also showed significantly increased infiltration of CD-20-positive immunocompetent cells compared with the controls. On the other hand, immunohistochemical examination found no significant differences in the number of IL-10- or TGF-β-positive cells. Conclusion: Ethmoid sinus mucosa from IgG4-RD-associated CRS patients showed clearly increased AID production, suggesting AID involvement in class-switching to IgG4 in those local sites. This implies the existence of a distinct form of CRS that is an IgG4-RD.

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