Koshi Yamada
Kei Ogiwara1
Jan Novak
Yusuke Suzuki- 1Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
- 2Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
IgA nephropathy (IgAN) is a mesangioproliferative glomerulonephritis characterized by IgA1-containing immune-complex deposits wherein IgA1 is enriched for galactose-deficient IgA1 (Gd-IgA1) glycoforms. IgAN pathogenesis involves mucosal immune system, as IgAN onset and activity are associated with infections of the upper-respiratory tract, i.e., synpharyngitic hematuria. Current four-hit hypothesis postulates that multiple events, starting with the production of Gd-IgA1, in genetically susceptible individuals lead to the formation of nephritogenic immune complexes and development of IgAN. Biochemical studies using IgA1-producing cell lines derived from the peripheral blood of IgAN patients and healthy controls revealed that secretion of Gd-IgA1 is due to dysregulated expression of several O-glycosylation enzymes. Production of Gd-IgA1 can be further upregulated by some cytokines. Genome-wide association studies identified multiple candidate genes for IgAN, serum levels of IgA, and serum levels of Gd-IgA1. Some of the IgAN-associated genes are also found in other autoimmune diseases and conditions. Notably, HORMAD2/LIF locus is associated with IgAN, serum levels of IgA, and tonsillectomy. In this review, we detail various findings concerning IgAN and Gd-IgA1 production by cells derived from the circulation and tonsils. Also, as tonsillectomy is commonly used in Japan as a part of treatment for IgAN, we detail biochemical and signaling studies of IgA1-producing cells derived from peripheral blood and tonsils.
1 Introduction
The daily production of IgA is the largest of all immunoglobulin (Ig) isotypes in humans, with a daily synthesis of up to 70 mg of IgA per kg of body weight (1). IgA is secreted by IgA-producing cells in two main molecular forms (2, 3): monomeric IgA (mIgA) and dimeric IgA (dIgA). The latter has a joining chain (J-chain) that covalently connects two mIgA molecules by disulfide bridges between Cys residue in the tail segment of the IgA heavy chain and a Cys residue in J-chain. Molecular forms of J-chain-containing IgA are also called polymeric IgA, and in addition to dimeric IgA, other polymeric forms of IgA may have three or more mIgA molecules. In addition, secretory IgA (SIgA) is the main form of IgA found on mucosal surfaces; SIgA contains secretory component (SC) derived by proteolytic cleavage from the polymeric immunoglobulin receptor (PIGR) during transcytosis through mucosal epithelial cells. IgA is the second most common Ig in the peripheral blood (~2 mg/mL of serum), after IgG (~12 mg/mL of serum), and is mainly present as mIgA, with only 10% represented by dIgA. However, IgA is the most abundant Ig in external secretions on mucosal surfaces (e.g., tears, saliva, nasal secretions, gallbladder bile, and intestinal fluids and also in colostrum and milk) and is secreted locally as SIgA. Mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts are the sites with high level of IgA secretion and also the sites used for mucosal-pathogen invasion. Important roles of IgA in the immune-defense processes are based on the abundance of IgA and its ability to form polymers (i.e., two or more mIgA molecules connected by the J-chain) that can neutralize and eliminate pathogens (4). In humans, IgA exists in two subclasses, IgA1 and IgA2. Although the two subclasses exhibit a great degree of amino-acid sequence identity, substantial differences in glycosylation impart functional differences (5). Specifically, IgA2 has five N-glycans per heavy chain whereas IgA1 has two N-glycans per heavy chain. In addition, IgA1 has clustered O-glycans in the extended hinge region, whereas IgA2 has a shorter hinge region without any O-glycans (5, 6) (Figure 1).
Figure 1. Molecular forms of human IgA1 and IgA2 (monomeric, dimeric, secretory) and their hinge-region amino-acid sequences. Comparison of amino-acid sequences of human IgA1 (top) and IgA2 (bottom) hinge regions. Human IgA1 has nine Ser (S) and Thr (T) amino-acid residues (underlined) in the hinge region segment (between constant regions CH1 and CH2 of the heavy chains). Usually, three to six clustered O-glycans are attached per hinge region (the six commonly utilized sites shown in red). IgA2 hinge region is shorter compared to that of IgA1, does not have Ser and Thr residues, and, thus, IgA2 does not have O-glycans.
Serum IgA is produced mainly by plasma cells in the bone marrow; this IgA is predominantly a monomeric protein with a quaternary structure consisting of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds. In contrast, mucosal IgA, particularly dIgA with a J chain, is produced by plasma cells close to the epithelium (7–9). Notably, involvement of mucosal-tissue-induced IgA is suspected in patients with IgA nephropathy (IgAN), as the clinical disease onset and disease activity are often associated with upper-respiratory tract infection and inflammation and the glomerular immune-complex deposits contain mostly polymeric IgA (1).
The concepts of homing and recirculation of IgA-producing cells have been emerging from various studies. It is known that IgA-producing B cells in the small intestine, including Peyer’s patches, express CCR9 and integrin α4β7 and the homing to the small intestine is impacted by retinoic acid produced by the local dendritic cells (10). Furthermore, 7α,25-dihydroxycholesterol produced by epithelial cells has additional effects of IgA-producing cells and IgA secretion (11). IgA antibodies against enterococci are detected in the feces, but not in the serum, of B6 mice kept under specific-pathogen free (SPF) conditions (12). These observations suggest that IgA-producing cells induced in the intestinal tract are usually homing to the intestinal mucosa and not to the bone marrow. The recirculation and homing are impacted by B-cell differentiation, isotype switching, responsiveness to chemoattractants, as well as cell-surface glycosylation (13). For example, a subset of B lymphocytes within secondary lymphoid organs responds to stromal cell-derived factor (SDF)-1α; this responsiveness correlates with specific localization within this lymphoid organ and is further controlled by the differentiation state of the cells and the involvement of the B-cell receptor (BCR) (14).
Genome-wide association studies (GWAS) identified multiple IgAN-associated loci, some of which are also associated with other diseases, including those characterized by disruption of the intestinal-epithelial barrier, IgA production, tonsillar infections, and abnormal responses to the gut microbiota. These findings thus support an important role for the mucosal immune responses in IgAN (15). Furthermore, the recently observed clinical improvement in IgAN patients treated with the controlled intestinal release formulation of budesonide (Tarpeyo) (16, 17), supports the notion that the pathogenic IgA in IgAN may be related to the cells originating in the intestinal mucosa. Tarpeyo is designed to be released locally in the distal ileum and proximal large intestine to decrease the production of pathogenic IgA by the IgA1-producing cell in the mucosal lymphoid tissue (Peyer’s patches). A phase III trial evaluating Tarpeyo for treatment of IgAN showed a significant reduction in short-term proteinuria and has resulted in accelerated FDA approval for use in the United States (17, 18).
In the situation when the intestinal mucosa is exposed to chronic inflammation, such as in inflammatory bowel disease, antigen-specific IgA of mucosal origin may appear in the circulation (19–21). As some patients with IgAN have a chronic inflammatory bowel disease, question arises about a possible connection between the two diseases. And, conversely, what differentiates those patients with both diseases from those with persistent inflammatory bowel disease who do not develop IgAN?
In this context, questions remain regarding the factors involved in the production of IgA and the possibility that plasma cells producing pathogenic IgA1 may not always originate from the intestinal mucosa. For example, experimental and clinical data linking tonsillitis and IgAN indicate involvement of tonsillar IgA-producing cells (22). B cells induced by nasopharyngeal-associated lymphoid tissue (NALT) may not only be homing to NALT and bronchus-associated lymphoid tissue (BALT), but also to other mucosal and lymphoid tissues that are involved in immune responses (23, 24). The “Mucosa-Bone marrow axis” hypothesis was proposed in the 1980s (25), based on the presence of polymeric IgA1-containing complexes in the serum and glomerular immunodeposits of patients with IgAN. Polymeric IgA is thought to be produced mainly by plasma cells in the mucosal tissues near the mucosal surfaces. The “Mucosa-Bone marrow axis” hypothesis postulates that nephritis-inducing IgA1-producing cells are induced in the mucosa and then migrate into the bone marrow to produce pathogenic IgA1 that initiates and sustains the disease. This hypothesis is supported by the finding that J-chain-containing IgA1-producing plasma cells are elevated in the bone marrow of IgAN patients (26).
IgA1 accounts for 85%-90% of serum IgA and is also produced by plasma cells (PCs) in the different tissues, including intestine, lungs, tonsils and nasal mucosa, whereas IgA2 is predominant in the colonic mucosa (27). Mucosa-associated bacteria often produce IgA-specific proteases that cleave amino acids in the hinge region of IgA1. In contrast, IgA2 is resistant to such cleavage by most of these proteases due to the differences in the hinge-region amino-acid sequence (28). Compared to IgA1, IgA2 activates neutrophils and macrophages more potently, which is thought to aid in efficient defense against infection (5). Conversely, it is IgA1 subclass that is involved in the formation of pathogenic immune complexes (29), and it is speculated that B cells induced in the NALT, including the tonsils, are involved.
It should be noted that clinical surveys of clinical presentation of IgAN in Europe and Japan indicated differences in the association of gastrointestinal complications with IgAN: for 17% of IgAN patients in Europe compared to 1% in Japan. Conversely, no significant difference in the incidence of macroscopic hematuria associated with upper-respiratory-tract infections was observed for IgAN patients in Japan (29.8%) vs. Europe (22.7%) (30).
2 IgAN, Gd-IgA1, and tonsils
IgAN is the most common primary glomerulonephritis in the world, with kidney failure occurring in most patients (31, 32). Considering that polymeric IgA1 is predominantly produced in mucosal tissues and a common clinical feature of IgAN is macroscopic hematuria associated with upper-respiratory tract infection, a possible link between the mucosal immune system and IgAN has been proposed (33, 34). Moreover, it is also not uncommon for urinary-tract abnormalities to occur after tonsillar irritation (35).
Subsequently, a search for IgAN-linked bacterial, viral, and/or food antigens has been undertaken, only to find no such generalized IgAN-specific agents (1, 36). Based on the accumulated data about the IgA1-containing immune complexes in the circulation of IgAN patients, biosynthesis of galactose-deficient IgA1 (Gd-IgA1), and IgG autoantibodies specific for Gd-IgA1 (37–44), the “multi-hit hypothesis” was proposed in 2011. This hypothesis on the pathobiology of IgAN has been widely accepted; it postulates that Gd-IgA1 glycoforms are bound in an immune complex with Gd-IgA1-specific IgG autoantibodies (45). Additional proteins are added and some of these complexes deposit in the glomeruli, causing kidney damage; serum levels of Gd-IgA1 and IgG autoantibodies are associated with disease progression (44, 46–48). Studies with cultured primary human mesangial cells showed that immune complexes consisting of IgA1 immune complexes (IgA1-IC) of molecular mass greater than 700 kDa induce cellular proliferation. Furthermore, the IgA1-IC isolated from serum of patients with active disease exhibiting macroscopic hematuria induced cellular proliferation of cultured mesangial cells to a higher degree than did the IgA1-IC isolated from sera of the same patients during a period of quiescent disease (40). Similarly, cultured mesangial cells incubated with serum IgA1 from IgAN patients activate extracellular signal-regulated kinase (ERK) of the mitogen-activated protein (MAP) kinase family, non-receptor type tyrosine kinase spleen tyrosine kinase (Syk) activation, and, subsequently, elevate production of proinflammatory cytokines and components of extracellular matrix (49–51).
Biochemical studies using IgA1-secreting cell lines derived from peripheral blood of IgAN patients and healthy controls revealed that Gd-IgA1 production is driven by altered biosynthetic pathways of IgA1 O-glycans (52). The clustered O-glycans of circulatory IgA1 are diverse in terms of their numbers per hinge region, attachments sites, and composition (Figure 2a). Biosynthesis of IgA1 O-glycans occurs in the Golgi apparatus of IgA1-producing cells (Figure 2b). IgA1-secreting cell lines from IgAN patients showed reduced expression of C1GALT1, its chaperone C1GALT1C1, and increased expression of ST6GALNAC2 (42). These gene-expression changes are associated with reduced Gal content in IgA1 secreted by IgA1-producing cells in IgAN patients (42). Notably, Gd-IgA1 in the circulation and glomerular immune-complex deposits of IgAN patients appears to be mainly in the polymeric form. Genetic studies showed that serum levels of Gd-IgA1 are genetically co-determined and GWAS identified genetic variations that impact the expression of C1GALT1 and C1GALT1C1 genes (53, 54). Moreover, expression of the glycosyltransferase C1GalT1 and the chaperon C1GalT1C1 can be altered by some pro-inflammatory cytokines (55–57).
Figure 2. O-glycosylation of human IgA1. (a) O-linked glycans of circulatory IgA1 are diverse in terms of their number, attachment sites, and composition. The Tn antigen (N-acetylgalactosamine; GalNAc) is usually modified by a specific galactosyltransferase (T-synthase, C1GalT1) in the Golgi apparatus. (b) IgA1 O-glycosylation pathways. The stepwise process begins with the attachment of GalNAc to some of the Ser/Thr residues in the hinge region catalyzed by a GalNAc-transferase(s) (GalNAc-T). GalNAc residues can be then modified by addition of Gal, mediated by core 1 β1,3- galactosyltransferase (C1GalT1). Production of the active C1GalT1 enzyme depends on its chaperone (C1GalT1C1, Cosmc). The core 1 structures (GalNAc-Gal) of IgA1 can be further modified by sialyltransferases that attach sialic acid to Gal (mediated by an ST3Gal enzyme, e.g., ST3Gal1) and/or GalNAc residues (mediated by an ST6GalNAc2 enzyme). Sialylation of GalNAc is mediated by ST6GalNAc2, as ST6GalNAc1 is not expressed in IgA1-producing cells (5). Conversely, if terminal GalNAc is sialylated by ST6GalNAc2, this structure cannot be further modified. Abnormal glycosylation of IgA1 is associated with dysregulated expression/activities of specific glycosyltransferases in IgA1-producing cells in patients with IgAN (42).
Although some of the biochemical pathways involved in the production of Gd-IgA1 have been determined, the origin and locations of the IgA1-producing cells secreting polymeric Gd-IgA1 remain to be clarified. Although the gut mucosa has abundance of IgA1-producing cells, tonsillar B cells have also been proposed as a possible source of Gd-IgA1 (58). When considering the role of palatine tonsils in the pathogenesis of IgAN in general and Gd-IgA1 production in particular, we have to consider several concepts and ask various questions. For example, what factors affect the supply of circulatory IgA1 and Gd-IgA1 by the cells residing in tonsils? Are those Gd-IgA1-producing cells generated in the tonsils and then migrate to different locations? How are these cells maintained and renewed? In the sections below, we are discussing some of these points and evaluate the current knowledge and hypotheses within the framework of the genetic and geographic factors impacting disease heterogeneity.
3 Palatine tonsils as secondary lymph nodes in upper-respiratory tract mucosal immunity
The palatine tonsils, together with the pharyngeal tonsils, Eustachian tube tonsils, lingual tonsils, and pharyngeal lateral wall lymph follicles, are lymphoid tissues that with an annular arrangement in the pharynx are collectively known as the Waldeyer’s tonsil ring. The palatine tonsils belong to the mucosa-associated lymphoid tissue (MALT) and are involved in the primary immune response to airborne and gastrointestinal pathogens introduced via the oral or nasal cavity, resulting in antibody production (59–61). The palatine tonsils, the major organ of the NALT, have four specialized tissue compartments—namely, reticulo-epithelium, extrafollicular region, mantle zone of lymph follicles, and follicular germinal center (GC)—that take part in the immune functions (59). The palatine tonsils have B-lymphocyte-dominant lymphocytes and a small number of myelomonocytic cells. Palatine tonsils do not have an afferent lymphatic network as other lymphoid organs (e.g., lymph nodes). Human palatine tonsils have approximately 15 crypts that increase the surface area to enable access of antigens to lymphoid tissue after passage through a specialized epithelium. Recent RNA-seq analyses have revealed that the palatine tonsils represent a highly specialized form of mucosa-associated lymphoid tissue that is distinct from other secondary lymphoid organs. In particular, reticular cells within the tonsils exhibit unique transcriptional profiles and spatial organization adapted to the environment of persistent antigen exposure at the oropharyngeal mucosa, and have been shown to play a critical role in the local regulation of T-cell and B-cell immune responses (62, 63). Dendritic cells take up exogenous antigens and transport them to extrafollicular T-cell areas and B-cell follicles (64). Antigen-presenting naive B cells are activated in the extrafollicular region. Some of these B cells undergo clonal proliferation, somatic hypermutation, affinity maturation, immunoglobulin class switching, and finally differentiate into plasma cells or memory B cells (59). Palatine tonsils undergo morphological, histopathological, and immunological changes with age: the size of palatine tonsils is prominent in childhood but decreases with age (65, 66). Histopathologically, parenchymal and lymph follicular areas decrease with age, while fibrous connective tissue, collagen fibers and elastic-fiber areas increase with age (67). Immunologically, the proportion of germinal center B cells decreases with age and the proportion of memory B cells increases with age. Ig isoforms preferentially switch from IgM to IgA with age (68).
Tonsillar lymphocytes proliferate ex vivo and synthesize DNA even when cultured in the absence of mitogens; B cells exhibit a high-production capacity for IgG and IgA (69, 70). These findings indicate that, unlike the peripheral-blood and peripheral-lymph-node lymphocytes, the tonsillar lymphocytes are enriched for activated B cells.
Moreover, the immune responses of the tonsils are aimed against pathogens and do not respond to tonsil-resident bacteria, such as alpha streptococci Streptococcus sanguinis, S. salivarius, and S. mitis, due to the immune-tolerance mechanisms (71). However, a DNA sequence common to all bacteria, unmethylated CpG-oligodeoxynucleotide (CpG-ODN) is a ligand for TLR9 that induces an innate immune response. TLRs mediate signaling to lymphocytes through inflammatory cytokines and maturation of dendritic cells, thus playing important roles in mucosal immunity (72, 73). Activation of the innate immune system may increase the production of nephritogenic IgA, independent of the specific antigen. Nasal stimulation in a mouse model of spontaneous IgAN with the TLR9 ligand CpG-ODN leads to exacerbated renal damage and increase in serum IgA levels and IgA mesangial deposits. The severity of glomerular damage in this model is related to the degree of TLR9 expression in splenocytes (74). In the tonsils of IgAN patients, immune tolerance is disrupted and there may be an excessive immune response to indigenous bacteria and their antigens, including bacterial DNA. These findings in a mouse model raise the question whether TLR9 may be involved in the pathogenesis of human IgAN, as discussed below.
4 Contribution of tonsillar B cells to circulatory IgA in IgAN
As noted before, polymeric serum IgA1 with aberrant O-glycosylation is implicated in the pathogenesis of IgAN as an autoantigen (45), and serum levels of Gd-IgA1 predict disease progression in IgAN (46, 48). In connection with the role of tonsillar cells in IgA production, it was reported that serum IgA levels decreased after tonsillectomy in patients with IgAN (75, 76). Furthermore polymeric-IgA-producing cells are elevated in the tonsils of IgAN patients (77), and cultured mitogen-stimulated tonsillar lymphocytes exhibit enhanced production of polymeric IgA (78). B-1 cells (CD19+,CD5+) may be the main type of IgA-producing cells in mucosal tissues (79), and these cells are increased in the germinal centers of tonsils of most IgAN patients (80). Notably, several studies reported that some but not all patients improved clinically in terms of reduced serum levels of IgA after tonsillectomy (81, 82); the patients who did not improve clinically after tonsillectomy did not have increased B-1 cells in the tonsillar GCs. IgA antibodies derived from B-1 cells against commensal bacteria are not natural antibodies but are specifically induced by antigenic stimulation. This also suggests that this pathway is independent of T cells and the organization of follicular lymphoid tissues (12, 83). It thus will be important to determine the role of B-1 cells in IgAN and their contribution to serum IgA in patients with IgAN.
Intra-tonsillar vaccination with tetanus vaccine induced IgG- and IgA-secreting cells; a fraction of B cells activated in tonsils entered the circulation and disseminated to distant organs and vaccine-specific antibodies were subsequently detected in serum and pharyngeal secretions (84). This and other studies thus demonstrated that tonsils could serve as inductive sites for immune responses in the upper-respiratory tract with physiological as well as pathophysiological implications (85–89).
Furthermore, elevated carriage of Neisseria species in the tonsils and increased presence of serum anti-Neisseria IgA was found in IgAN patients (90). Furthermore, transgenic mice with human B-cell activating factor (BAFF-Tg mice) after nasal infection with Neisseria developed elevated serum levels of anti-Neisseria IgA, and anti-Neisseria IgA-secreting cells were found in the kidneys. This finding indicates that IgA-producing cells induced by exogenous antigen exposure in the airways may migrate to other sites, including the kidneys (90). Although the functional capacities of these B cells are not fully understood, it is likely that they cells undergo a maturation process during the GC response.
The IgA1 circulating in the blood and deposited in the glomeruli of patients with IgAN is enriched for aberrantly glycosylated IgA1, Gd-IgA1. Gd-IgA1 is also produced by tonsillar mononuclear cells, and the tonsils may be an important site of Gd-IgA1 production in some patients (91, 92). In addition, IL-6 or leukemia inhibitory factor (LIF) stimulate the tonsil-derived IgA1-producing cell lines from IgAN patients, as well as their peripheral-blood-derived IgA1 cells, to overproduce Gd-IgA1 due to abnormal signal transducer and activator of transcription 3 (STAT3) or signal transducer and activator of transcription 1 (STAT1) signaling (93–95). Elevated activation of STAT1 in the peripheral-blood mononuclear cells and kidney tissues of IgAN patients is associated with proteinuria but not with disease progression (96).
Activation of TLRs can induce a class switch of B cells to IgA in the absence of T cells via cytokines, such as BAFF and a proliferation-inducing ligand (APRIL) (97). In IgAN patients, increased APRIL expression in tonsillar GCs is associated with increased TLR9 expression and with worse urinary findings. TLR9 involvement in the pathogenesis of IgAN may be mediated via the APRIL pathway, leading to plasma-cell maturation (22). Stimulation of tonsillar mononuclear cells from patients with IgAN with CpG-ODN induces T cell-independent production of BAFF, IFN-γ, and IgA (98). BAFF increases Bcl-2 expression in B cells, that inhibits B cell apoptosis (99). Interestingly, Bcl-2 can increase the production of abnormally glycosylated IgA1 and promote renal glomerular IgA deposition (100). BAFF overproduction mediated by CpG-ODN in tonsils of IgAN patients may be involved in qualitative as well as quantitative abnormalities of IgA1.
In clinical studies, TLR9 hyper-expression in tonsils is associated with higher efficacy of tonsillectomy combined with steroid-pulse therapy (101); reports of TLR9 gene polymorphism being associated with the pathogenesis of IgAN is in line with the proposed CpG-ODN-TLR9 pathway (74). Moreover, expression of TLR7 in tonsils is upregulated in IgAN patients and correlates with the expression of APRIL, adding another TLR-mediated pathway to the list (102). In addition, increased expression of various TLRs in peripheral-blood monocytes has been observed in patients with IgAN, indicating a chronic activation of innate immunity in IgAN patients (103, 104).
5 Tonsillectomy as a treatment for IgAN
In Japan, the combination of tonsillectomy and steroid-pulse therapy has frequently resulted in clinical remission (defined by negative results for urinary occult blood and protein), and this therapy is commonly used for Japanese IgAN patients (105–107). To investigate the possible association between tonsillectomy and outcomes in patients with IgAN, a multicenter analysis of 1,065 patients (with a mean follow-up time of 5.8 years) was performed with a primary endpoint of 1.5-fold increase in serum creatinine and initiation of dialysis; propensity-score matching showed a 57-66% risk reduction in the tonsillectomy group compared to the no-tonsillectomy group (108). With these results, The Kidney Disease: Improving Global Outcomes (KDIGO) 2025 guidelines (https://www.sciencedirect.com/journal/kidney-international/vol/108/issue/4/suppl/S) have been revised and indicate that tonsillectomy should be considered in Japan on an individual-case basis. In examining predictors, tonsillectomy and/or corticosteroids therapy in patients with eGFR <60 mL/min/1.73 m2 and urinary protein <0.5 g/day tended to reduce cumulative outcome incidence compared to other types of treatment, i.e., not including corticosteroids and tonsillectomy (109). In addition, a report from a randomized prospective study (J-IGACS) showed that adding tonsillectomy to systemic corticosteroid therapy was associated with a 60% risk reduction of renal events in IgAN patients (110). Notably, no long-term negative effects of tonsillectomy on immune function have been observed (111, 112).
In the clinical context, it is well known that in patients with IgAN, tonsillectomy decreases serum IgA levels, with an average reduction of about 10% in one study (101). Comparison of groups with greater vs. smaller reduction in serum IgA levels after tonsillectomy revealed a possible association with TLR9 – patients with high TLR9 expression in the tonsils exhibited greater reduction of serum IgA levels after tonsillectomy (101). This observation is in line with the hypothesis that some of the nephritis-inducing IgA1 (i.e., Gd-IgA1) may be related to tonsillar B cells and involve TLR pathways. In another study, IgAN patients who had Gd-IgA1 serum levels reduced after tonsillectomy exhibited a greater reduction of hematuria compared to the patients whose serum Gd-IgA1 were not reduced after tonsillectomy. Moreover, tonsillar TLR9 expression levels were high in IgAN patients who exhibited reduction in serum Gd-IgA1 levels after tonsillectomy (58). Furthermore, tonsillectomy performed in the first year after renal transplantation reduced the level of serum Gd-IgA1 and the recurrence rate of histological IgAN (113). These findings suggest that serum Gd-IgA1 from tonsillar B cells may play an important role in the development of IgAN.
With respect to the multi-hit hypothesis for IgAN, are any of these observations relevant to the production of IgG autoantibodies specific for Gd-IgA1? Given the variation in the glycosylation of the hinge region of IgA1 and of the cloned IgG antibodies, it is likely that immune complexes are formed by polyclonal IgG autoantibodies rather than by an autoantibody produced by a single clone of B cells (27). What is the localization of the cells producing these autoantibodies that drive the formation of pathogenic immune complexes? Could tonsils be among the sites that harbor the cells producing these IgG autoantibodies? Are these autoantibodies formed in a T cell-dependent fashion? Interestingly, an increase in the number of B-1 cells in the tonsil GC was observed in IgAN patients who showed clinical improvement after tonsillectomy. In contrast, no increase in B-1 cells in tonsil GCs was observed in patients who did not improve after tonsillectomy (80). Furthermore, as B-1 cells are increased in the peripheral blood of patients with IgAN (114), it is possible that B cells involved in production of Gd-IgA1 and/or IgG autoantibodies may also migrate to or from the tonsils.
6 IgA, tonsillectomy, and IgAN: findings from GWAS and signaling studies
GWAS of IgAN in patients of Asian and European ancestry revealed multiple candidate genes with many of those known to participate in regulation of mucosal immune responses (15, 115–124). The latest GWAS revealed 30 loci associated with the risk of IgAN (125). Among the candidate genes were those that regulate mucosal-associated lymphoid tissues involved in IgA production, such as ITGAM and TNFSF13 (Figure 3). From the top 26 high-priority ‘biological candidates’, 11 can be targeted directly or indirectly by existing drugs. Some candidate drugs are in various clinical trials. These drugs include: (a) inhibitors of the alternative or lectin complement pathway, currently in clinical trials for different types of glomerulopathies (126, 127). The complement targets applicable to IgAN include MASP-2, complement factors B and D, C3, C5, and C5a receptors 1 (C5aR1) (128). (b) Drugs targeting B cells by inhibiting APRIL or its receptors, e.g., transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), are already in clinical trials for IgAN. A recent clinical trial reported that administration of TACI-IgG Fc fusion protein (Atacicept), an inhibitor of APRIL, to IgAN patients reduced serum levels of Gd-IgA1 and improved proteinuria (129). Similarly, a humanized IgG2 monoclonal antibody (Sibeprenlimab), a neutralizing antibody for APRIL, has also been reported to reduce serum levels of Gd-IgA1 and improve proteinuria (130). Unfortunately, most of the IgAN-associated causal genes with the risk alleles increasing the gene expression, such as CARD9, ITGAX, PF4V1, CFHR1 or FCAR, do not yet have effective drug inhibitors (125).
Figure 3. Pathogenesis of IgA nephropathy (IgAN) and the associated IgAN-susceptibility genetic loci. IgAN is thought to involve immune-system stimulation by foreign antigens related to the upper-respiratory tract and gastrointestinal tract infections. These processes involve T cell-dependent and independent pathways enhancing the production of Gd-IgA1, with baseline-Gd-IgA1 production being genetically co-determined. APRIL and BAFF enable isotype switch in B cells, leading to plasmacytoid differentiation and elevated Gd-IgA1 production that can be also enhanced by IL-6 and LIF due to abnormal JAK/STAT signaling (Hit 1). In genetically susceptible individuals, autoantibodies specific for Gd-IgA1 are produced (Hit 2), driving production of immune complexes that have additional proteins added (Hit 3). Some of these complexes deposit in the glomeruli, activate mesangial cells, leading to kidney injury (Hit 4). Various humoral factors produced by the activated mesangial cells also induce podocyte injury and tubulointerstitial damage, and contribute to the development of nephritis. NALT, Nasal-associated lymphoid tissue; GALT, Gut-associated lymphoid tissue; TLR, Toll-like receptor; BAFF, B-cell activating factor belonging to the Tumor-Necrosis Family; APRIL, A proliferation-inducing ligand; Gd-IgA1, Galactose-deficient IgA1; JAK/STAT, Janus kinase/signal transducer and activator of transcription; SFK, Src-family kinase; RAS, Renin-Angiotensin-Aldosterone System; GWAS, genome-wide association studies; HLA-DQA1, major histocompatibility complex, class II, DQ α 1; HLA-DQB1, major histocompatibility complex, class II, DQ β 1; HLA-DRB1, major histocompatibility complex, class II, DR β 1; FCRC3, Fc receptor like 3; TNFSF13, Tumor Necrosis Factor Superfamily, Member 13; DEFA, Defensin α; CARD9, Caspase recruitment domain-containing protein 9; HORMAD2, HORMA Domain Containing 2; LIF, Leukemia inhibitory factor; VAV3, Vav Guanine Nucleotide Exchange Factor 3; ITGAM/ITGAX, Integrin α M/Integrin α X; CFH, Complement factors H; CFHR3,1, Complement Factor H Related 3,1.
HORMAD2 IgAN-associated locus contains multiple genes, including LIF and oncostatin M (OSM). This locus is also associated with tonsillectomy and IgA serum levels (124, 131) and its biological effects may include TLR9 pathways (132). Notably, LIF is a high-scoring drug-target gene (125). The cytokines LIF and IL-6, when bound to receptor complexes comprising gp130/LIF receptor and gp130/IL-6 receptor, respectively, activate JAK/STAT pathways and alter the expression of several genes (57).
In the IgA1-producing cell lines derived from peripheral blood of patients with IgAN, aberrant STAT1 signaling mediated by LIF was associated with Gd-IgA1 overproduction. Moreover, kinomic studies revealed that baseline activities of several protein tyrosine kinases (PTKs) in IgA1-producing cells from IgAN patients were higher than those in cells from healthy controls (HC). Most of these PTKs were associated with growth factors Eph and Src, signaling pathways related to cell growth, transcription factors, and cross-activation of PTK receptors. Furthermore, LIF activation further increased activities of PTKs in the Src family in IgA1-producing cells from IgAN patients but not in the cells from HC. Conversely, in the cells from HC, LIF activated fibroblast growth factor receptors (FGFR), platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) systems (94).
Whereas LIF signaling in IgA1-secreting cells derived from peripheral blood utilizes STAT1, IL-6 signaling exclusively uses STAT3. Furthermore, IgA1-secreting cells from peripheral blood from patients with IgAN are abnormally activated by IL-6 compared to those from HC. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3 in the cells from patients with IgAN, a process that results in overproduction of Gd-IgA1. Analysis of nine independent STAT3 ChIP-seq datasets derived from B cells identified multiple STAT3-binding sites located both upstream and downstream of the C1GALT1 locus, a key glycosyltransferase gene encoding enzyme involved in galactosylation of IgA1 O-glycans. These findings provide further insight into a potential regulatory mechanism of C1GALT1 mediated by IL-6/STAT3 signaling. Notably, transcription of C1GALT1 is known to be critically dependent on SP1/3 binding to its promoter region (133). In this context, activated STAT3 may exert a negative regulatory effect by interfering with SP1/3-mediated transcriptional activity. Such a mechanism is consistent with previous observations demonstrating downregulation of C1GALT1 transcription following IL-6 stimulation (56). This IL-6-mediated overproduction of Gd-IgA1 is inhibited by Stattic, a specific STAT3 inhibitor, and AZD1480, a JAK2 small molecule inhibitor, in a dose-dependent manner (93).
As B cells from the peripheral blood may differ in many characteristics from those in lymphatic tissues, we expanded our studies to include IgA1-producing cells from the palatine tonsils. Using IgA1-producing cell lines derived from the tonsils of IgAN patients and disease controls (obstructive sleep apnea), we determined that LIF stimulation leads to Gd-IgA1 overproduction, but only in the tonsillar cell lines of IgAN patients (95). This LIF-induced Gd-IgA1 overproduction in IgAN-derived tonsillar cells was mediated by STAT1, as confirmed by STAT1 siRNA knock-down. Moreover, a JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction, further confirming that LIF utilizes JAK2/STAT1 signaling pathway. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with obstructive sleep apnea. Although IL-6 also induced overproduction of Gd-IgA1 in the IgA1-producing cell lines derived from the tonsils of IgAN patients, JAK2 inhibitors did not reduce overproduction of Gd-IgA1 to that of controls.
In summary, IgA1-producing cells from patients with IgAN exhibit abnormal responses to at least two cytokines of the IL-6 family: IL-6 and LIF. Each of these two cytokines uses a different STAT protein for signal transduction: IL-6 uses STAT3 whereas LIF signals are mediated by STAT1. Moreover, IgA1-producing cells lines derived from tonsils vs. the circulation exhibit differences in LIF/LIFR/JAK2/STAT1 signaling pathways, underscoring differential characteristics of IgA1-secreting cells from peripheral blood vs. lymphatic tissues. Moreover, identifying the cell populations upstream of the IL-6/LIF signaling pathway as well as the microenvironment that drives Gd-IgA1 production—particularly the interactions between stromal cells and immune cells within mucosa-associated lymphoid tissue—represent critical challenges for follow-up studies.
Further studies will need to elucidate how these functional differences may impact IgAN and what implications there may be for the use of tonsillectomy in Japan with respect to the time interval from disease onset/diagnosis.
7 Conclusion
In this review, we have described mucosal immune abnormalities in IgAN with an emphasis on the upper-airway mucosa and the origins and pathways leading to the production of aberrantly glycosylated IgA1, Gd-IgA1 (Figure 4). Multiple findings collectively suggest that these pathogenic glycoforms of IgA1 are produced by IgA1-secreting cells originating from or residing in mucosal tissues, e.g., gut and tonsils, and that some growth factors and cytokines activate these cells and induce overproduction of Gd-IgA1. NALT and gut-associated lymphoid tissue (GALT) are the main sites with IgA-producing cells and both may exhibit abnormal immune responses relevant to IgAN (134). For example, in experimental model systems of intestinal mucosa, loss of STAT3 signaling disrupted the mucosal barrier, causing differentiation of cells forming the progenitor cell niche and abnormal proliferation of progenitor cells (135). Furthermore, aberrant LIF-mediated STAT1 signaling in tonsillar cells enhances Gd-IgA1 production. These phenomena, together with GWAS data, provide clues that will lead to elucidating the origin of IgA1-producing cells and pathological mechanisms of IgAN.
Figure 4. Cellular and molecular mechanisms of tonsillar mucosal immunity contributing to the pathogenesis of IgA nephropathy (IgAN). This schematic illustrates how chronic mucosal antigen stimulation in the tonsils leads to the generation of pathogenic IgA responses and subsequent glomerular injury in IgAN in susceptible individuals. In the left panel, recurrent exposure to mucosal antigens, such as bacterial DNA (CpG) and viral RNA, activates TLR9/TLR7 signaling and BAFF/APRIL pathways in the tonsils, initiating local immune responses. The central panel depicts a pathogenic tonsillar niche, in which B-cell receptor (BCR) signaling cooperates with TLR9/TLR7 activation, leading to the induction of IL-6– and LIF-mediated JAK–STAT signaling. These pathways drive aberrant IgA class switching and increased production of galactose-deficient IgA1 (Gd-IgA1). Naive B cells differentiate into IgA+ B cells and IgA+ plasma cells, resulting in amplification of pathogenic IgA responses. The second panel from the right illustrates the hypothesis on mucosa–bone marrow axis, whereby Gd-IgA1–producing plasmablasts migrate to the bone marrow through CXCR4 and α4β1 integrin–dependent homing mechanisms, establishing a sustained source of circulating Gd-IgA1. However, Gd-IgA1-producing cells may also migrate to other tissues, including the lungs and intestine. In the far-right panel, circulating Gd-IgA1-containing immune complexes deposit in the glomerular mesangium, inducing mesangial cell proliferation, matrix expansion, and production of pro-inflammatory cytokines, ultimately resulting in glomerular injury. This schematic figure was created using an AI-assisted image generation tool (ChatGPT, OpenAI) and were subsequently edited by the authors.
Author contributions
KY: Writing – original draft, Writing – review & editing, Conceptualization, Investigation. KO: Writing – review & editing. JN: Writing – review & editing. YS: Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. KY and YS are supported in part by Grant-in-Aid for Scientific Research (C) KAKENHI 25K11527. This work was supported in part by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan. JN is supported in part by research-acceleration funds from UAB and a gift from the IGA Nephropathy Foundation. The funder was not involved in the study design,collection,analysis, interpretationof data, the writing of this article or the decision to submit it for publication.
Conflict of interest
JN and YS are co-inventors on US patent application 14/318,082assigned to The UAB Research Foundation UABRF and licensed byUABRF to Reliant Glycosciences, LLC. JN is a co-founder and coownerof and consultant for Reliant Glycosciences, LLC. JN receivedhonoraria fromCalliditas Therapeutics, Travere Therapeutics, NovartisPharma, and Vera Therapeutics. JN reports sponsored researchagreements with Argenx via UAB. YS has served as a consultant forOtsuka Pharmaceutical, Novartis Pharma, Argenx, BioCrystPharmaceuticals, Alexion Pharmaceuticals, Renalys Pharma, AlpineImmune Sciences, and George Clinical, and has received honorariafrom Kyowa Kirin, Novartis Pharma, Mitsubishi Tanabe Pharma,Otsuka Pharmaceutical, Daiichi Sankyo, AstraZeneca,Boehringer Ingelheim.
The remaining author(s) declared that this work was conductedin the absence of any commercial or financial relationships thatcould be construed as a potential conflict of interest.
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References
1. Novak J, Julian BA, Tomana M, and Mestecky J. Progress in molecular and genetic studies of IgA nephropathy. J Clin Immunol. (2001) 21:310–27. doi: 10.1023/a:1012284402054
2. Mestecky J, Russell MW, Jackson S, and Brown TA. The human IgA system: a reassessment. Clin Immunol Immunopathol. (1986) 40:105–14. doi: 10.1016/0090-1229(86)90073-5
3. Conley ME and Delacroix DL. Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med. (1987) 106:892–9. doi: 10.7326/0003-4819-106-6-892
4. Phalipon A, Cardona A, Kraehenbuhl JP, Edelman L, Sansonetti PJ, and Corthésy B. Secretory component: a new role in secretory IgA-mediated immune exclusion. Vivo Immun. (2002) 17:107–15. doi: 10.1016/S1074-7613(02)00341-2
5. Reily C, Stewart TJ, Renfrow MB, and Novak J. Glycosylation in health and disease. Nat Rev Nephrol. (2019) 15:346–66. doi: 10.1038/s41581-019-0129-4
6. Hansen AL, Reily C, Novak J, and Renfrow MB. Immunoglobulin A glycosylation and its role in disease. Exp Suppl. (2021) 112:433–77. doi: 10.1007/978-3-030-76912-3_14
7. Koshland ME. The coming of age of the immunoglobulin J chain. Annu Rev Immunol. (1985) 3:425–53. doi: 10.1146/annurev.iy.03.040185.002233
8. Guzman M, Lundborg LR, Yeasmin S, Tyler CJ, Zgajnar NR, Taupin V, et al. An integrin αEβ7-dependent mechanism of IgA transcytosis requires direct plasma cell contact with intestinal epithelium. Mucosal Immunol. (2021) 14:1347–57. doi: 10.1038/s41385-021-00439-x
9. Pracht K, Wittner J, Kagerer F, Jäck HM, and Schuh W. The intestine: a highly dynamic microenvironment for IgA plasma cells. Front Immunol. (2023) 14:1114348. doi: 10.3389/fimmu.2023.1114348
10. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science. (2006) 314:1157–60. doi: 10.1126/science.1132742
11. Ceglia S, Berthelette A, Howley K, Li Y, Mortzfeld B, Bhattarai SK, et al. An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells. Nat Immunol. (2023) 24:531–44. doi: 10.1038/s41590-022-01413-w
12. Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, and Zinkernagel RM. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science. (2000) 288:2222–6. doi: 10.1126/science.288.5474.2222
13. Prakash S, Steers NJ, Li Y, Sanchez-Rodriguez E, Verbitsky M, Robbins I, et al. Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy. J Clin Invest. (2025) 135(10):e181164. doi: 10.1172/jci181164
14. Bleul CC, Schultze JL, and Springer TA. B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state, and B cell receptor engagement. J Exp Med. (1998) 187:753–62. doi: 10.1084/jem.187.5.753
15. Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. (2014) 46:1187–96. doi: 10.1038/ng.3118
16. Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, De Fijter JW, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. (2017) 389:2117–27. doi: 10.1016/S0140-6736(17)30550-0
17. Lafayette R, Kristensen J, Stone A, Floege J, Tesař V, Trimarchi H, et al. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NEFIGARD): 2-year results from a randomised phase 3 trial. Lancet. (2023) 402:859–70. doi: 10.1016/S0140-6736(23)01554-4
18. Ghaddar M, Barratt J, and Barbour SJ. An update on corticosteroid treatment for IgA nephropathy. Curr Opin Nephrol Hypertens. (2023) 32:263–70. doi: 10.1097/MNH.0000000000000881
19. Melcher C, Schramm CA, Kampe L, Zhang Y, Westphal K, Krautkrämer M, et al. Inflammatory modalities shape the IgA repertoire via stochastic processes. Cell Rep. (2025) 44:116307. doi: 10.1016/j.celrep.2025.116307
20. Dingess KA, Hoek M, Van Rijswijk DMH, Tamara S, Den Boer MA, Veth T, et al. Identification of common and distinct origins of human serum and breastmilk IgA1 by mass spectrometry-based clonal profiling. Cell Mol Immunol. (2023) 20:26–37. doi: 10.1038/s41423-022-00954-2
21. Novak J, Renfrow MB, King RG, Reily C, and Green TJ. Protein-based profiling of the human IgA1 clonal repertoire revealed shared clones of serum polymeric IgA1 and milk secretory IgA1. Cell Mol Immunol. (2023) 20:305–7. doi: 10.1038/s41423-022-00965-z
22. Muto M, Manfroi B, Suzuki H, Joh K, Nagai M, Wakai S, et al. Toll-like receptor 9 stimulation induces aberrant expression of a proliferation-inducing ligand by tonsillar germinal center B cells in IgA nephropathy. J Am Soc Nephrol. (2017) 28:1227–38. doi: 10.1681/ASN.2016050496
23. Kiyono H and Fukuyama S. NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat Rev Immunol. (2004) 4:699–710. doi: 10.1038/nri1439
24. Brandtzaeg P. Potential of nasopharynx-associated lymphoid tissue for vaccine responses in the airways. Am J Respir Crit Care Med. (2011) 183:1595–604. doi: 10.1164/rccm.201011-1783OC
25. Van Den Wall Bake AW, Daha MR, Evers-Schouten J, and Van Es LA. Serum IgA and the production of IgA by peripheral blood and bone marrow lymphocytes in patients with primary IgA nephropathy: evidence for the bone marrow as the source of mesangial IgA. Am J Kidney Dis. (1988) 12:410–4. doi: 10.1016/S0272-6386(88)80036-2
26. Harper SJ, Pringle JH, Wicks AC, Hattersley J, Layward L, Allen A, et al. Expression of J chain mRNA in duodenal IgA plasma cells in IgA nephropathy. Kidney Int. (1994) 45:836–44. doi: 10.1038/ki.1994.110
27. Brandtzaeg P and Johansen FE. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev. (2005) 206:32–63. doi: 10.1111/j.0105-2896.2005.00283.x
28. Brandtzaeg P, Baekkevold ES, Farstad IN, Jahnsen FL, Johansen FE, Nilsen EM, et al. Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol Today. (1999) 20:141–51. doi: 10.1016/S0167-5699(98)01413-3
29. Conley ME, Cooper MD, and Michael AF. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus. J Clin Invest. (1980) 66:1432–6. doi: 10.1172/JCI109998
30. Suzuki Y, Monteiro RC, Coppo R, and Suzuki H. The phenotypic difference of IgA nephropathy and its race/gender-dependent molecular mechanisms. Kidney360. (2021) 2:1339–48. doi: 10.34067/KID.0002972021
31. Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, et al. Long-term outcomes in IgA nephropathy. Clin J Am Soc Nephrol. (2023) 18:727–38. doi: 10.2215/CJN.0000000000000135
32. Sim JJ, Chen Q, Cannizzaro N, Fernandes AW, Pinto C, Bhandari SK, et al. CKD progression, kidney failure, and mortality among US patients with IgA nephropathy. Nephrol Dial Transplant. (2025) 40:2104–17. doi: 10.1093/ndt/gfaf084
33. Wyatt RJ and Julian BA. IgA nephropathy. N Engl J Med. (2013) 368:2402–14. doi: 10.1056/NEJMra1206793
34. Kiryluk K and Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Invest. (2014) 124:2325–32. doi: 10.1172/JCI74475
35. Xie Y, Chen X, Nishi S, Narita I, and Gejyo F. Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy. Kidney Int. (2004) 65:1135–44. doi: 10.1111/j.1523-1755.2004.00486.x
36. Russell MW, Mestecky J, Julian BA, and Galla JH. IgA-associated renal diseases: antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin Immunol. (1986) 6:74–86. doi: 10.1007/BF00915367
37. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, and Mestecky J. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. (1999) 104:73–81. doi: 10.1172/JCI5535
38. Novak J, Vu HL, Novak L, Julian BA, Mestecky J, and Tomana M. Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int. (2002) 62:465–75. doi: 10.1046/j.1523-1755.2002.00477.x
39. Moura IC, Arcos-Fajardo M, Sadaka C, Leroy V, Benhamou M, Novak J, et al. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol. (2004) 15:622–34. doi: 10.1097/01.ASN.0000115401.07980.0C
40. Novak J, Tomana M, Matousovic K, Brown R, Hall S, Novak L, et al. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. (2005) 67:504–13. doi: 10.1111/j.1523-1755.2005.67107.x
41. Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. (2007) 71:1148–54. doi: 10.1038/sj.ki.5002185
42. Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest. (2008) 118:629–39. doi: 10.1172/JCI33189
43. Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. (2008) 19:1008–14. doi: 10.1681/ASN.2007091052
44. Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. (2009) 119:1668–77. doi: 10.1172/JCI38468
45. Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. (2011) 22:1795–803. doi: 10.1681/ASN.2011050464
46. Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. (2012) 82:790–6. doi: 10.1038/ki.2012.197
47. Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C, et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol. (2012) 23:1579–87. doi: 10.1681/ASN.2012010053
48. Maixnerova D, Ling C, Hall S, Reily C, Brown R, Neprasova M, et al. Galactose-deficient IgA1 and the corresponding IgG autoantibodies predict IgA nephropathy progression. PloS One. (2019) 14:e0212254. doi: 10.1371/journal.pone.0212254
49. Tamouza H, Chemouny JM, Raskova Kafkova L, Berthelot L, Flamant M, Demion M, et al. The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int. (2012) 82:1284–96. doi: 10.1038/ki.2012.192
50. Kim MJ, McDaid JP, McAdoo SP, Barratt J, Molyneux K, Masuda ES, et al. Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients. J Immunol. (2012) 189:3751–8. doi: 10.4049/jimmunol.1102603
51. Liu P, Lassén E, Nair V, Berthier CC, Suguro M, Sihlbom C, et al. Transcriptomic and proteomic profiling provides insight into mesangial cell function in IgA nephropathy. J Am Soc Nephrol. (2017) 28:2961–72. doi: 10.1681/ASN.2016101103
52. Novak J, King RG, Yother J, Renfrow MB, and Green TJ. O-glycosylation of IgA1 and the pathogenesis of an autoimmune disease IgA nephropathy. Glycobiology. (2024) 34:cwae060. doi: 10.1093/glycob/cwae060
53. Kiryluk K, Li Y, Moldoveanu Z, Suzuki H, Reily C, Hou P, et al. GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PloS Genet. (2017) 13:e1006609. doi: 10.1371/journal.pgen.1006609
54. Gale DP, Molyneux K, Wimbury D, Higgins P, Levine AP, Caplin B, et al. Galactosylation of IgA1 is associated with common variation in C1GALT1. J Am Soc Nephrol. (2017) 28:2158–66. doi: 10.1681/ASN.2016091043
55. Yamada K, Kobayashi N, Ikeda T, Suzuki Y, Tsuge T, Horikoshi S, et al. Down-regulation of core 1 β1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1. Nephrol Dial Transplant. (2010) 25:3890–7. doi: 10.1093/ndt/gfq325
56. Suzuki H, Raska M, Yamada K, Moldoveanu Z, Julian BA, Wyatt RJ, et al. Cytokines alter IgA1 O-glycosylation by dysregulating C1GALT1 and ST6GALNAC-II enzymes. J Biol Chem. (2014) 289:5330–9. doi: 10.1074/jbc.M113.512277
57. Person T, King RG, Rizk DV, Novak J, Green TJ, and Reily C. Cytokines and production of aberrantly O-glycosylated IgA1, the main autoantigen in IgA nephropathy. J Interferon Cytokine Res. (2022) 42:301–15. doi: 10.1089/jir.2022.0039
58. Nakata J, Suzuki Y, Suzuki H, Sato D, Kano T, Yanagawa H, et al. Changes in nephritogenic serum galactose-deficient IgA1 in IgA nephropathy following tonsillectomy and steroid therapy. PloS One. (2014) 9:e89707. doi: 10.1371/journal.pone.0089707
59. Brandtzaeg P. Immunology of tonsils and adenoids: everything the ENT surgeon needs to know. Int J Pediatr Otorhinolaryngol. (2003) 67:S69–76. doi: 10.1016/j.ijporl.2003.08.018
60. van Kempen MJ, Rijkers GT, and Van Cauwenberge PB. The immune response in adenoids and tonsils. Int Arch Allergy Immunol. (2000) 122:8–19. doi: 10.1159/000024354
61. Surján L Jr. Tonsils and lympho-epithelial structures in the pharynx as immuno-barriers. Acta Otolaryngol. (1987) 103:369–72.
62. De Martin A, Stanossek Y, Lütge M, Cadosch N, Onder L, Cheng HW, et al. Pi16(+) reticular cells in human palatine tonsils govern T cell activity in distinct subepithelial niches. Nat Immunol. (2023) 24:1138–48. doi: 10.1038/s41590-023-01502-4
63. Lütge M, De Martin A, Gil-Cruz C, Perez-Shibayama C, Stanossek Y, Onder L, et al. Conserved stromal-immune cell circuits secure B cell homeostasis and function. Nat Immunol. (2023) 24:1149–60. doi: 10.1038/s41590-023-01503-3
64. Perry M and Whyte A. Immunology of the tonsils. Immunol Today. (1998) 19:414–21. doi: 10.1016/S0167-5699(98)01307-3
65. Akcay A, Kara CO, Dagdeviren E, and Zencir M. Variation in tonsil size in 4- to 17-year-old schoolchildren. J Otolaryngol. (2006) 35:270–4. doi: 10.2310/7070.2005.0118
66. Nave H, Gebert A, and Pabst R. Morphology and immunology of the human palatine tonsil. Anat Embryol. (2001) 204:367–73. doi: 10.1007/s004290100210
67. Harada K. The histopathological study of human palatine tonsils—especially age changes. Nihon Jibiinkoka Gakkai Kaiho. (1989) 92:1049–64. doi: 10.3950/jibiinkoka.92.1049
68. Lee J, Chang DY, Kim SW, Choi YS, Jeon SY, Racanelli V, et al. Age-related differences in human palatine tonsillar B cell subsets and immunoglobulin isotypes. Clin Exp Med. (2016) 16:81–7. doi: 10.1007/s10238-015-0338-5
69. Yamanaka N, Kobayashi K, Himi T, Shido F, and Kataura A. Spontaneous DNA synthesis in tonsillar lymphocytes and its clinical implications. Acta Otolaryngol. (1983) 96:181–7. doi: 10.3109/00016488309132890
70. Harabuchi Y, Hamamoto M, Kodama H, and Kataura A. Spontaneous immunoglobulin production by adenoidal and tonsillar lymphocytes in relation to age and otitis media with effusion. Int J Pediatr Otorhinolaryngol. (1996) 35:117–25. doi: 10.1016/0165-5876(95)01298-2
71. Murakata H, Harabuchi Y, and Kataura A. Increased interleukin-6, interferon-gamma and tumour necrosis factor-alpha production by tonsillar mononuclear cells stimulated with alpha-streptococci in patients with pustulosis palmaris et plantaris. Acta Otolaryngol. (1999) 119:384–91. doi: 10.1080/00016489950181431
72. Iwasaki A and Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. (2004) 5:987–95. doi: 10.1038/ni1112
73. Akira S, Uematsu S, and Takeuchi O. Pathogen recognition and innate immunity. Cell. (2006) 124:783–801. doi: 10.1016/j.cell.2006.02.015
74. Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. (2008) 19:2384–95. doi: 10.1681/ASN.2007121311
75. Masuda Y, Tamura S, and Sugiyama N. The effect of tonsillectomy and its postoperative clinical course in IgA nephropathy with chronic tonsillitis. Adv Otorhinolaryngol. (1992) 47:203–7. doi: 10.1159/000421745
76. Tomioka S, Miyoshi K, Tabata K, Hotta O, and Taguma Y. Clinical study of chronic tonsillitis with IgA nephropathy treated by tonsillectomy. Acta Otolaryngol Suppl. (1996) 523:175–7.
77. Nagy J and Brandtzaeg P. Tonsillar distribution of IgA and IgG immunocytes and production of IgA subclasses and J chain in tonsillitis vary with the presence or absence of IgA nephropathy. Scand J Immunol. (1988) 27:393–9. doi: 10.1111/j.1365-3083.1988.tb02362.x
78. Egido J, Blasco R, Lozano L, Sancho J, and Garcia-Hoyo R. Immunological abnormalities in the tonsils of patients with IgA nephropathy: inversion in the ratio of IgA: IgG-bearing lymphocytes and increased polymeric IgA synthesis. Clin Exp Immunol. (1984) 57:101–6.
79. Hiroi T, Yanagita M, Iijima H, Iwatani K, Yoshida T, Takatsu K, et al. Deficiency of IL-5 receptor alpha-chain selectively influences the development of the common mucosal immune system-independent IgA-producing B-1 cell in mucosa-associated tissues. J Immunol. (1999) 162:821–8. doi: 10.4049/jimmunol.162.2.821
80. Kodama S, Suzuki M, Arita M, and Mogi G. Increase in tonsillar germinal centre B-1 cell numbers in IgA nephropathy patients and reduced susceptibility to Fas-mediated apoptosis. Clin Exp Immunol. (2001) 123:301–8. doi: 10.1046/j.1365-2249.2001.01431.x
81. Iino Y, Ambe K, Kato Y, Nakai A, Toriyama M, Saima K, et al. Chronic tonsillitis and IgA nephropathy: clinical study of patients with and without tonsillectomy. Acta Otolaryngol Suppl. (1993) 508:29–35. doi: 10.3109/00016489309130263
82. Sugiyama N, Shimizu J, Nakamura M, Kiriu T, Matsuoka K, and Masuda Y. Clinicopathological study of the effectiveness of tonsillectomy in IgA nephropathy accompanied by chronic tonsillitis. Acta Otolaryngol Suppl. (1993) 508:43–8. doi: 10.3109/00016489309130265
83. Bos NA, Bun JC, Popma SH, Cebra ER, Deenen GJ, Van Der Cammen MJ, et al. Monoclonal immunoglobulin A derived from peritoneal B cells is encoded by both germ line and somatically mutated VH genes and is reactive with commensal bacteria. Infect Immun. (1996) 64:616–23. doi: 10.1128/iai.64.2.616-623.1996
84. Quiding-Järbrink M, Granström G, Nordström I, Holmgren J, and Czerkinsky C. Induction of compartmentalized B-cell responses in human tonsils. Infect Immun. (1995) 63:853–7. doi: 10.1128/iai.63.3.853-857.1995
85. Bemark M and Angeletti D. Know your enemy or find your friend? Induction of IgA at mucosal surfaces. Immunol Rev. (2021) 303:83–102. doi: 10.1111/imr.13014
86. Harabuchi Y and Takahara M. Recent advances in the immunological understanding of association between tonsil and IgA nephropathy as a tonsil-induced autoimmune/inflammatory syndrome. Immun Inflammation Dis. (2019) 7:86–93. doi: 10.1002/iid3.248
87. Palkola NV, Blomgren K, Pakkanen SH, Puohiniemi R, Kantele JM, and Kantele A. Immune defense in upper airways: a single-cell study of pathogen-specific plasmablasts and their migratory potentials in acute sinusitis and tonsillitis. PloS One. (2016) 11:e0154594. doi: 10.1371/journal.pone.0154594
88. Brandtzaeg P. Secretory immunity with special reference to the oral cavity. J Oral Microbiol. (2013) 5:20401. doi: 10.3402/jom.v5i0.20401
89. Boyaka PN, Wright PF, Marinaro M, Kiyono H, Johnson JE, Gonzales RA, et al. Human nasopharyngeal-associated lymphoreticular tissues: functional analysis of subepithelial and intraepithelial B and T cells from adenoids and tonsils. Am J Pathol. (2000) 157:2023–35. doi: 10.1016/S0002-9440(10)64841-9
90. Currie EG, Coburn B, Porfilio EA, Lam P, Rojas OL, Novak J, et al. Immunoglobulin A nephropathy is characterized by anticommensal humoral immune responses. JCI Insight. (2022) 7:e141289. doi: 10.1172/jci.insight.141289
91. Horie A, Hiki Y, Odani H, Yasuda Y, Takahashi M, Kato M, et al. IgA1 molecules produced by tonsillar lymphocytes are under-O-glycosylated in IgA nephropathy. Am J Kidney Dis. (2003) 42:486–96. doi: 10.1016/S0272-6386(03)00743-1
92. Inoue T, Sugiyama H, Hiki Y, Takiue K, Morinaga H, Kitagawa M, et al. Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy. Clin Immunol. (2010) 136:447–55. doi: 10.1016/j.clim.2010.05.009
93. Yamada K, Huang ZQ, Raska M, Reily C, Anderson JC, Suzuki H, et al. Inhibition of STAT3 signaling reduces IgA1 autoantigen production in IgA nephropathy. Kidney Int Rep. (2017) 2:1194–207. doi: 10.1016/j.ekir.2017.07.002
94. Yamada K, Huang ZQ, Raska M, Reily C, Anderson JC, Suzuki H, et al. Leukemia inhibitory factor signaling enhances production of galactose-deficient IgA1 in IgA nephropathy. Kidney Dis (Basel). (2020) 6:168–80. doi: 10.1159/000505748
95. Yamada K, Huang ZQ, Reily C, Green TJ, Suzuki H, Novak J, et al. LIF/JAK2/STAT1 signaling enhances production of galactose-deficient IgA1 by IgA1-producing cell lines derived from tonsils of patients with IgA nephropathy. Kidney Int Rep. (2024) 9:423–35. doi: 10.1016/j.ekir.2023.11.003
96. Tao J, Mariani L, Eddy S, Maecker H, Kambham N, Mehta K, et al. JAK-STAT activity in peripheral blood cells and kidney tissue in IgA nephropathy. Clin J Am Soc Nephrol. (2020) 15:973–82. doi: 10.2215/CJN.11010919
97. He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity. (2007) 26:812–26. doi: 10.1016/j.immuni.2007.04.014
98. Goto T, Bandoh N, Yoshizaki T, Nozawa H, Takahara M, Ueda S, et al. Increase in B-cell-activation factor and IFN-gamma productions by tonsillar mononuclear cells stimulated with CpG-ODN in patients with IgA nephropathy. Clin Immunol. (2008) 126:260–9. doi: 10.1016/j.clim.2007.11.003
99. Saito Y, Miyagawa Y, Onda K, Nakajima H, Sato B, Horiuchi Y, et al. B-cell-activating factor inhibits CD20-mediated and B-cell receptor-mediated apoptosis in human B cells. Immunology. (2008) 125:570–90. doi: 10.1111/j.1365-2567.2008.02872.x
100. Marquina R, Díez MA, López-Hoyos M, Buelta L, Kuroki A, Kikuchi S, et al. Inhibition of B cell death causes the development of IgA nephropathy in (New Zealand White × C57BL/6)F1-Bcl-2 transgenic mice. J Immunol. (2004) 172:7177–85. doi: 10.4049/jimmunol.172.11.7177
101. Sato D, Suzuki Y, Kano T, Suzuki H, Matsuoka J, Yokoi H, et al. Tonsillar TLR9 expression and efficacy of tonsillectomy with steroid pulse therapy in IgA nephropathy patients. Nephrol Dial Transplant. (2012) 27:1090–7. doi: 10.1093/ndt/gfr403
102. Lee M, Suzuki H, Ogiwara K, Aoki R, Kato R, Nakayama M, et al. The nucleotide-sensing Toll-like receptor 9/Toll-like receptor 7 system is a potential therapeutic target for IgA nephropathy. Kidney Int. (2023) 104:943–55. doi: 10.1016/j.kint.2023.08.013
103. Coppo R, Camilla R, Amore A, Peruzzi L, Daprà V, Loiacono E, et al. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with IgA nephropathy. Clin Exp Immunol. (2010) 159:73–81. doi: 10.1111/j.1365-2249.2009.04045.x
104. Donadio ME, Loiacono E, Peruzzi L, Amore A, Camilla R, Chiale F, et al. Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch–Schönlein purpura and primary IgA nephropathy. Pediatr Nephrol. (2014) 29:1545–51. doi: 10.1007/s00467-014-2807-6
105. Hotta O, Miyazaki M, Furuta T, Tomioka S, Chiba S, Horigome I, et al. Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy. Am J Kidney Dis. (2001) 38:736–43. doi: 10.1053/ajkd.2001.27690
106. Komatsu H, Fujimoto S, Hara S, Sato Y, Yamada K, and Kitamura K. Effect of tonsillectomy plus steroid pulse therapy on clinical remission of IgA nephropathy: a controlled study. Clin J Am Soc Nephrol. (2008) 3:1301–7. doi: 10.2215/CJN.00310108
107. Kawamura T, Yoshimura M, Miyazaki Y, Okamoto H, Kimura K, Hirano K, et al. A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with IgA nephropathy. Nephrol Dial Transplant. (2014) 29:1546–53. doi: 10.1093/ndt/gfu020
108. Hirano K, Matsuzaki K, Yasuda T, Nishikawa M, Yasuda Y, Koike K, et al. Association between tonsillectomy and outcomes in patients with IgA nephropathy. JAMA Netw Open. (2019) 2:e194772. doi: 10.1001/jamanetworkopen.2019.4772
109. Shirai S, Yasuda T, Kumagai H, Matsunobu H, Ichikawa D, Shibagaki Y, et al. Prognostic factors of IgA nephropathy presenting with mild proteinuria at the time of diagnosis (a multicenter cohort study). Clin Exp Nephrol. (2023) 27:340–8. doi: 10.1007/s10157-023-02316-2
110. Kawamura T, Hirano K, Koike K, Nishikawa M, Shimizu A, Joh K, et al. Associations of corticosteroid therapy and tonsillectomy with kidney survival in a multicenter prospective study for IgA nephropathy. Sci Rep. (2023) 13:18455. doi: 10.1038/s41598-023-45514-4
111. Bitar MA, Dowli A, and Mourad M. The effect of tonsillectomy on the immune system: a systematic review and meta-analysis. Int J Pediatr Otorhinolaryngol. (2015) 79:1184–91. doi: 10.1016/j.ijporl.2015.05.016
112. Mitchell RB, Archer SM, Ishman SL, Rosenfeld RM, Coles S, Finestone SA, et al. Clinical practice guideline: tonsillectomy in children (update). Otolaryngol Head Neck Surg. (2019) 160:S1–S42. doi: 10.1177/0194599818801757
113. Kawabe M, Yamamoto I, Yamakawa T, Katsumata H, Isaka N, Katsuma A, et al. Association between galactose-deficient IgA1 derived from the tonsils and recurrence of IgA nephropathy in patients who underwent kidney transplantation. Front Immunol. (2020) 11:2068. doi: 10.3389/fimmu.2020.02068
114. Yuling H, Ruijing X, Xiang J, Yanping J, Lang C, Li L, et al. CD19+CD5+ B cells in primary IgA nephropathy. J Am Soc Nephrol. (2008) 19:2130–9. doi: 10.1681/ASN.2007121303
115. Feehally J, Farrall M, Boland A, Gale DP, Gut I, Heath S, et al. HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol. (2010) 21:1791–7. doi: 10.1681/ASN.2010010076
116. Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. (2011) 43:321–7. doi: 10.1038/ng.787
117. Yu XQ, Li M, Zhang H, Low HQ, Wei X, Wang JQ, et al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet. (2011) 44:178–82. doi: 10.1038/ng.1047
118. Kiryluk K, Li Y, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, Eitner F, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PloS Genet. (2012) 8:e1002765. doi: 10.1371/journal.pgen.1002765
119. Li M, Foo JN, Wang JQ, Low HQ, Tang XQ, Toh KY, et al. Identification of new susceptibility loci for IgA nephropathy in Han Chinese. Nat Commun. (2015) 6:7270. doi: 10.1038/ncomms8270
120. Qi YY, Zhou XJ, Cheng FJ, Hou P, Zhu L, Shi SF, et al. DEFA gene variants associated with IgA nephropathy in a Chinese population. Genes Immun. (2015) 16:231–7. doi: 10.1038/gene.2015.1
121. Zhong Z, Feng SZ, Xu RC, Li ZJ, Huang FX, Yin PR, et al. Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population. J Gene Med. (2017) 19:e2966. doi: 10.1002/jgm.2966
122. Shi M, Ouyang Y, Yang M, Yang M, Zhang X, Huang W, et al. IgA nephropathy susceptibility loci and disease progression. Clin J Am Soc Nephrol. (2018) 13:1330–8. doi: 10.2215/CJN.13701217
123. Li M, Wang L, Shi DC, Foo JN, Zhong Z, Khor CC, et al. Genome-wide meta-analysis identifies three novel susceptibility loci and reveals ethnic heterogeneity of genetic susceptibility for IgA nephropathy. J Am Soc Nephrol. (2020) 31:2949–63. doi: 10.1681/ASN.2019080799
124. Liu L, Khan A, Sanchez-Rodriguez E, Zanoni F, Li Y, Steers N, et al. Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits. Nat Commun. (2022) 13:6859. doi: 10.1038/s41467-022-34456-6
125. Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, Zanoni F, Liu L, Mladkova N, et al. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nat Genet. (2023) 55:1091–105. doi: 10.1038/s41588-023-01422-x
126. Zipfel PF, Wiech T, Rudnick R, Afonso S, Person F, and Skerka C. Complement inhibitors in clinical trials for glomerular diseases. Front Immunol. (2019) 10:2166. doi: 10.3389/fimmu.2019.02166
127. Rizk DV, Maillard N, Julian BA, Knoppova B, Green TJ, Novak J, et al. The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol. (2019) 10:504. doi: 10.3389/fimmu.2019.00504
128. Caravaca-Fontán F, Gutiérrez E, Sevillano ÁM, and Praga M. Targeting complement in IgA nephropathy. Clin Kidney J. (2023) 16:ii28–39. doi: 10.1093/ckj/sfad198
129. Barratt J, Tumlin J, Suzuki Y, Kao A, Aydemir A, Pudota K, et al. Randomized phase II JANUS study of atacicept in patients with IgA nephropathy and persistent proteinuria. Kidney Int Rep. (2022) 7:1831–41. doi: 10.1016/j.ekir.2022.05.017
130. Mathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, et al. A phase 2 trial of sibeprenlimab in patients with IgA nephropathy. N Engl J Med. (2024) 390:20–31. doi: 10.1056/NEJMoa2305635
131. Feenstra B, Bager P, Liu X, Hjalgrim H, Nohr EA, Hougaard DM, et al. Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy. J Med Genet. (2017) 54:358–64. doi: 10.1136/jmedgenet-2016-104304
132. Wang YN, Gan T, Qu S, Xu LL, Hu Y, Liu LJ, et al. MTMR3 risk alleles enhance Toll-like receptor 9-induced IgA immunity in IgA nephropathy. Kidney Int. (2023) 104:562–76. doi: 10.1016/j.kint.2023.06.018
133. Zeng J, Mi R, Wang Y, Li Y, Lin L, Yao B, et al. Promoters of human COSMC and T-synthase genes are similar in structure, yet different in epigenetic regulation. J Biol Chem. (2015) 290:19018–33. doi: 10.1074/jbc.M115.654244
134. Kano T, Suzuki H, Makita Y, Nihei Y, Fukao Y, Nakayama M, et al. Mucosal immune system dysregulation in the pathogenesis of IgA nephropathy. Biomedicines. (2022) 10:3027. doi: 10.3390/biomedicines10123027
Keywords: a proliferation-inducing ligand (APRIL), galactose-deficient IgA1 (Gd-IgA1), genome-wide association studies (GWAS), IgA nephropathy, leukemia inhibitory factor (LIF), nasal-associated lymphoid tissue (NALT), toll-like receptor 9 (TLR9), tonsillectomy
Citation: Yamada K, Ogiwara K, Novak J and Suzuki Y (2026) Aberrant signaling in tonsillar B cells producing pathogenic O-glycoforms of IgA1 in IgA nephropathy. Front. Immunol. 17:1737992. doi: 10.3389/fimmu.2026.1737992
Received: 02 November 2025; Accepted: 09 January 2026; Revised: 17 December 2025;
Published: 30 January 2026.
Edited by:
Xingmin Sun, University of South Florida, United StatesReviewed by:
Honghui Zeng, The First Affiliated Hospital of Nanchang University, ChinaKazuo Takahashi, Fujita Health University, Japan
Copyright © 2026 Yamada, Ogiwara, Novak and Suzuki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yusuke Suzuki, eXVzdWtlQGp1bnRlbmRvLmFjLmpw