IntroductionImmunoglobulin A nephropathy (IgAN) is a chronic glomerular disease characterized by mesangial IgA deposition, which can progress to end-stage renal failure. Tonsillectomy is used as a therapeutic intervention to slow disease progression and provide early clinical benefit. However, the immune mechanisms within the palatine tonsils that contribute to IgAN pathogenesis remain incompletely understood.MethodsTo define the tonsillar immune environment that regulates pathological antibody production, we analyzed T and B lymphocyte subsets in relation to renal function. We also conducted functional studies to evaluate the production of galactose-deficient IgA (Gd-IgA) and anti-Tn (GalNAc-Ser/Thr) antibodies, both of which are implicated in the formation of pathogenic immune complexes.ResultsInterfollicular T follicular helper (IF-Tfh) cells (CD3+CD4+CD8-PD-1loCXCR5lo) were significantly expanded in IgAN tonsils compared with disease controls and strongly correlated with clinical markers of renal abnormalities. Transcriptomic analysis of IF-Tfh cells from IgAN tonsils revealed a distinct gene expression profile enriched for effector memory T cell–like features associated with kidney impairment. Functional studies demonstrated that IF-Tfh cells potently promoted class-switched memory B cells to produce Gd-IgA1 and anti-Tn (GalNAc-Ser/Thr) antibodies.ConclusionThese findings suggest that an IF-Tfh cell–dominant immune environment drives IgAN pathogenesis and may represent a target for noninvasive therapeutic approaches.

OBJECTIVES:IgG4-related disease (IgG4-RD) has long been associated with Th2-predominant immune responses and allergic features. However, the immunological context underlying lesional Th2-like inflammation remains incompletely understood. METHODS:Bulk RNA-seq data from 49 submandibular gland lesions of IgG4-RD were analyzed. Module scores representing Th2, Tfh/Tph, B cell, germinal center B cell (GC_B), plasma cell, macrophage and stromal/fibrotic programmes were calculated. Correlations between Th2 module scores and other immune/stromal modules were assessed using Spearman correlation analysis. Differentially expressed genes between Th2-high and Th2-low lesions were also evaluated. RESULTS:Th2 module scores were strongly associated with Tfh, Tfh/Tph and Tph helper T cell programmes, as well as with B cell, GC_B and plasma cell signatures. In addition, Th2 module scores positively correlated with M2 macrophage and fibrosis-associated macrophage (FAM) programmes. Differential expression analysis demonstrated increased expression of chronic helper T cell-related genes, including PDCD1, TOX and MAF, together with plasmablast-associated genes such as JCHAIN, MZB1 and PRDM1 in Th2-high lesions. In contrast, serum IgG4 and IgE levels did not significantly differ between Th2-high and Th2-low groups. CONCLUSIONS:Lesional Th2-like inflammation in IgG4-RD was closely associated with chronic Tfh/Tph-germinal center immune programmes linked to plasmablast and M2/FAM macrophage responses. No clear association with available systemic allergy-related parameters was observed in this cohort.

OBJECTIVE:To evaluate perioperative changes in olfactory bulb volume (OBV) and olfactory function in patients with eosinophilic chronic rhinosinusitis (ECRS) using 3T magnetic resonance imaging (MRI) with fast imaging employing steady-state acquisition (FIESTA) sequence and to assess their associations. METHODS:This single-center, retrospective observational study included 32 patients with ECRS who underwent functional endoscopic sinus surgery. Olfactory function was assessed pre- and postoperatively using the Alinamin test, T&T olfactometer, Open Essence (OE), Odor Stick Identification Test for Japanese (OSIT-J), Visual Analog Scale (VAS), and Self-Assessment Olfactory Questionnaire (SAOQ). OBV was manually measured from FIESTA images. Logistic regression was used to identify preoperative predictors of OBV change. RESULTS:Postoperative OE, OSIT-J, VAS, and SAOQ scores improved significantly. Mean OBV increased by 10.3% postoperatively, although not statistically significant (p = 0.095). OBV change correlated with improvements in olfactory identification (OE: r = 0.404, p = 0.022; OSIT-J: r = 0.402, p = 0.022), which should be interpreted as exploratory. Multivariate analysis revealed that longer odor duration on the Alinamin test (≥ 50 s) and higher SAOQ scores predicted smaller OBV increases. CONCLUSION:OBV measurement using 3T MRI with FIESTA may provide a structural correlate of olfactory changes in ECRS. The observed correlation between OBV changes and olfactory identification suggests a potential relationship with postoperative functional recovery. LEVEL OF EVIDENCE: 4:

OBJECTIVES:IgG4-related disease (IgG4-RD) predominantly affects middle-aged and elderly individuals; however, the impact of aging on lesional immune architecture remains poorly understood. METHODS:Bulk transcriptomic analyses were performed using IgG4-RD lesion tissues across a broad age spectrum. Age-associated genes, Hallmark pathways, and immune/stromal module scores were evaluated using correlation-based analyses, network analysis, and fibrosis pseudo-staging. RESULTS:Principal component analysis demonstrated age-associated transcriptomic shifts in IgG4-RD lesions. Aging was associated with increased expression of cytotoxic/exhaustion-related genes, including IFNG, GZMA, GZMH, and PRDM1, together with activation of inflammaging- and senescence-associated programs. Module analysis demonstrated positive correlations between age and fibroblast, exhaustion, macrophage/M2, fibrosis-associated macrophage (FAM), inflammaging, and senescence-associated secretory phenotype (SASP) signatures, whereas germinal center B-cell programs showed minimal association with age. Hallmark pathway analysis revealed enrichment of interferon-γ response, IL6-JAK-STAT3 signaling, TNFα/NFκB signaling, epithelial-mesenchymal transition, and TGF-β signaling in aging lesions. Network analysis demonstrated segregation between adaptive immune modules and aging-associated fibro-inflammatory modules. Advanced fibrosis pseudo-stages were enriched in older patients. CONCLUSIONS:Aging in IgG4-RD was associated with coordinated immune ecosystem remodeling characterized by inflammaging, exhaustion-associated immune programs, stromal activation, and relative reduction in the prominence of adaptive germinal center immunity. These findings suggest that aging-associated immune remodeling may contribute to chronic fibro-inflammatory disease evolution in IgG4-related dacryoadenitis and sialadenitis.

OBJECTIVES:IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder affecting multiple organs, but the extent to which immune microenvironments differ across tissues remains unclear. We compared immune cell compositions between submandibular gland and pancreatic lesions using transcriptome-based deconvolution analysis. METHODS:Bulk RNA sequencing data were obtained from patients with IgG4-related submandibular sialadenitis (n = 40) and autoimmune pancreatitis (n = 8). Immune cell fractions were estimated using CIBERSORTx with the LM22 immune signature matrix. Relative immune cell compositions were compared descriptively, and exploratory Mann-Whitney U tests with false discovery rate (FDR) adjustment were performed. RESULTS:Both tissues shared broad immune cell repertoires, including B cells, T cells, macrophages, dendritic cells, mast cells, and natural killer cells, indicating a common immune framework across IgG4-RD lesions. However, organ-specific differences in relative immune cell abundance were observed. Pancreatic lesions showed a tendency toward increased macrophage populations, particularly M1-like macrophages, together with relatively reduced naïve B-cell fractions. In contrast, submandibular gland lesions demonstrated relatively enriched B-cell populations, including naïve and memory B cells, with a more balanced macrophage distribution. These patterns were consistently observed across samples and supported by deconvolution confidence metrics. CONCLUSIONS:IgG4-RD lesions share common immunological features while exhibiting differences in relative immune cell composition across tissues. Pancreatic lesions tended to show relatively increased macrophage fractions, whereas submandibular gland lesions demonstrated a more lymphocyte-rich immune profile. These findings suggest that local tissue context may shape immune composition and contribute to clinical heterogeneity in IgG4-RD.

OBJECTIVES:To identify therapeutic candidates for IgG4-related sialadenitis, a manifestation of IgG4-related disease characterized by IgG4-positive plasma cell infiltration and limited treatment options beyond glucocorticoids, using transcriptomic profiling and in silico drug repurposing. METHODS:Submandibular gland tissues from 49 patients with IgG4-related sialadenitis and 3 controls were analyzed by RNA sequencing. Differentially expressed genes were screened against DrugBank to identify druggable targets. Candidate drugs were prioritized based on their ability to modulate disease-associated gene signatures. Molecular docking was performed to evaluate binding affinities to key targets. RESULTS:Transcriptomic analysis revealed upregulation of immune-related pathways. DrugBank integration identified fostamatinib as a top candidate targeting multiple kinases, including SYK, BTK, and JAK3. Docking analysis demonstrated favorable binding affinity, particularly to BTK. CONCLUSION:This integrative approach highlights fostamatinib as a promising therapeutic candidate and supports a role for the SYK-BTK axis in IgG4-RD pathogenesis, suggesting a potential alternative to glucocorticoids.

Objective Birch pollen is the predominant tree pollen allergen in Hokkaido, Japan, and is frequently associated with oral allergy syndrome (OAS). However, most previous studies have been hospital-based, and population-level data remain limited. Methods We conducted a cross-sectional questionnaire survey of residents of Hokkaido recruited through 10 medical institutions and their family members. Data were collected on physician-diagnosed birch pollinosis, oral allergy symptoms after food ingestion, demographic factors, residential area, and comorbid allergic diseases. Associations were evaluated using chi-square tests, odds ratios (OR) with 95% confidence intervals (CI), and multivariate logistic regression analyses. Results A total of 3615 residents were included. The prevalence of physician-diagnosed birch pollinosis was 15.21%, higher than that of other pollen allergies. In multivariate analysis, residential area was an independent determinant of birch pollinosis, with significantly higher odds in northern, central, and eastern Hokkaido than in southern Hokkaido. Female sex, age, perennial allergic rhinitis and food allergy were also independently associated with birch pollinosis.Oral allergy symptoms were reported by 22.41% of participants and occurred in 66.55% of individuals with birch pollinosis. In the multivariate model for oral allergy symptoms, birch pollinosis was a strong independent factor, with additional associations observed for female sex, age, perennial allergic rhinitis and atopic dermatitis. Conclusions Birch pollinosis and OAS are highly prevalent in Hokkaido. Oral allergy symptoms are strongly linked to birch pollinosis, supporting OAS as a characteristic clinical manifestation of birch pollen sensitization in birch-endemic regions.

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by progressive organ damage; however, the spatial organization linking immune dysregulation to fibrotic remodeling remains incompletely understood. In this study, we performed spatial transcriptomic analysis of submandibular gland tissues from patients with IgG4-RD representing two distinct fibrosis-associated tissue states. Gene expression data were normalized and z-scored, and immune- and fibrosis-related module scores were calculated. Fibrotic niches were defined based on COL1A1 expression and fibroblast signatures, and spatial co-localization and correlation analyses were conducted. Fibrosis-high tissue regions exhibited enrichment of SPP1-expressing macrophages that co-localized with COL1A1 and fibroblast-rich areas, consistent with a spatially defined fibrotic niche. These regions were associated with increased expression of PDGFB and TGF-β–related molecules, which correlated with fibrosis-related signatures. Immune network analysis suggested remodeling of the immune microenvironment, with expansion and integration of Tph-associated populations. A preTfh-to-Tph axis became more apparent in fibrosis-high lesions, accompanied by reduced germinal center B-cell signatures and enhanced extrafollicular activation. Exhaustion-associated programs, including PDCD1 and TOX, were associated with T-cell differentiation states and SPP1-related signatures. Together, these findings identify an SPP1-associated immune–fibrotic niche and suggest a spatially coordinated relationship between immune remodeling and fibrosis in IgG4-RD. This hypothesis-generating framework provides insights into fibrosis-associated tissue remodeling and may inform future strategies for disease stratification and therapeutic targeting.

Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by IgG4-positive plasma cell infiltration and ectopic lymphoid structure formation. Although glucocorticoids are effective, relapse rates and adverse effects highlight the need for novel therapeutic targets. The immunological basis of IgG4-RD remains incompletely understood. Methods We analyzed peripheral blood mononuclear cells and inflammatory cells from the affected submandibular glands of patients with IgG4-RD using FACS. We assessed T peripheral helper (Tph) cell subsets and CD11c+CD21- B cells and examined their associations with immunological and clinical parameters. Results Tph2 cells in peripheral blood and submandibular glands were significantly increased in patients with IgG4-RD, and circulating Tph2 cells expressed granzyme B, indicating their cytotoxic potential. Their frequency correlated positively with serum IgG4, soluble IL-2 receptor levels, plasmablast expansion, eosinophil counts, number of affected organs, and IgG4-RD Responder Index. CD11c+CD21- B cells were also expanded and enriched in IgG4-producing subsets. These cells showed strong correlations with serum IgG4 levels, the IgG4/IgG ratio, and disease activity, but were inversely related to T follicular helper cells. Notably, Tph2 cells exhibited a robust positive correlation with CD11c+CD21- B cells, defining a distinct extrafollicular immune axis. Glucocorticoid treatment reduced Tph2 frequencies in parallel with serum IgG4 decline. Conclusions This study identifies a novel Tph2–CD11c+CD21- B cell axis driving extrafollicular immune dysregulation in IgG4-RD. Tph2 cells link humoral activation with cytotoxicity, and CD11c+CD21- B cells serve as producers of IgG4 associated with disease severity. Targeting this axis may provide therapeutic strategies for refractory or relapsing IgG4-RD beyond glucocorticoids.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

Objective To identify genes that could provide clues leading to the discovery of drugs to treat IgG4-related disease (IgG4-RD).Methods Submandibular gland tissue bulk RNAseq analysis of 45 cases with a definite diagnosis of IgG4-RD was integrated with Visium spatial transcriptome analysis of two cases to identify pathogenic genes expressed in tertiary lymphoid tissues.Results Bulk RNAseq and pathway analyses showed upregulation of cell cycle and T cell-related signals in IgG4-RD. Spatial transcriptome analysis identified the cluster corresponding to germinal centres and the top 38 common genes that showed significant variations in expression compared with other clusters. The top 20 genes were extracted by comparing the bulk RNAseq data. Network analysis identified CDK1 as the gene most strongly associated of the top 20 genes.Conclusion The CDK1 gene may be a regulator of the pathogenesis of IgG4-RD and provide clues for drug discovery.

OBJECTIVES:For the diagnosis of immunoglobulin G4 (IgG4)-related dacryoadenitis and sialadenitis, either revised comprehensive diagnostic criteria or organ-specific diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis in 2008 were applied; however, the collected knowledge for IgG4-related dacryoadenitis and sialadenitis required us to revise the criteria for IgG4-related dacryoadenitis and sialadenitis. METHODS:The board member of Japanese Study Group for IgG4-related Dacryoadenitis and Sialadenitis revised the diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis. We collected the clinical questions to be revised and performed a review of the literature. When the data were insufficient, additional data collection was performed. After the revision, public comments were collected. RESULTS:The three major points were revised. (1) Asymmetric or under two pairs of dacryoadenitis and sialadenitis were included as IgG4-related dacryoadenitis and sialadenitis. (2) The thresholds of IgG4-positive cell infiltration were adjusted to an IgG4+/IgG+ ratio >0.4 and IgG4+ cells >10 per high power field. (3) The labial salivary gland biopsy was allowed to diagnose IgG4-related dacryoadenitis and sialadenitis. CONCLUSIONS:The revised diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis solved several issues with the previous criteria. It will improve the early diagnosis of IgG4-related dacryoadenitis and sialadenitis, especially in situations without enough resources for a biopsy.

CD4+ T cells, the so-called T helper cells, are one of the main players in the human immune system, which can regulate acquired immunity. Dysfunction of the acquired immune system induces various chronic inflammatory diseases such as malignancies and autoimmune diseases. IgG4-related disease (IgG4-RD) is also a chronic inflammatory disease that is characterized by elevated serum IgG4 concentration and infiltration of IgG4-positive plasma cells in affected tissues. Despite that remarkable advances in understanding the pathogenesis of IgG4-RD have been on the rise, the detailed mechanisms by which IgG4-RD develops are still unknown. In fact, CD4+ T cells abundantly infiltrate at lesions of IgG4-RD, and they are also associated with the pathogenesis of other refractory chronic inflammatory diseases. Therefore, our focus was on CD4+ T cells, and we previously reported the roles of their subsets including regulatory T cells, CD4 cytotoxic T lymphocytes, T follicular helper (Tfh) cells, T follicular regulatory cells, and T peripheral helper (Tph) cells in IgG4-RD. Among the subsets, Tph cells play an important role in generating ectopic lymphoid structures at inflammatory sites. Moreover, we found that circulating Tph cells are increased in IgG4-RD patients. Unlike Tfh cells, Tph cells express high levels of chemokine receptors and cytotoxic molecules. Thus, they can infiltrate affected tissues and exert a cytotoxic function. Additionally, our latest observations demonstrated that Tph cells interact with extrafollicular B cells in affected tissues. Hence, Tph cells may collaborate with a specific B-cell subset, and they play a role in the maintenance of persistent fibroinflammation in lesions of IgG4-RD. Tph cells may have an important role to play in the pathogenesis of not only IgG4-RD but also other chronic inflammatory diseases. This review summarizes and discusses the possible pathologic roles of CD4+ T cell subsets including Tph cells in IgG4-RD.

ABSTRACT Objectives To identify the specific microRNAs (miRNAs) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) and predict the targeted genes. Methods miRNAs in the serum of nine patients with IgG4-DS, three patients with primary Sjögren’s syndrome, and three healthy controls were analysed using the human miRNA chip, and miRNAs that exhibited significant fluctuation in expression in IgG4-DS patients were extracted. The respective target genes were predicted using an existing database, and expression of the target genes was evaluated in actual submandibular gland tissues affected by IgG4-DS. Results Serum miR-125a-3p and miR-125b-1-3p levels were elevated in IgG4-DS. Six candidate target genes (glypican 4, forkhead box C1, protein tyrosine phosphatase non-receptor type 3, hydroxycarboxylic acid receptor 1, major facilitator superfamily domain containing 11, and tumour-associated calcium signal transducer 2) were downregulated in the affected submandibular gland tissue. Conclusion Overexpression of miR-125a-3p and miR-125b-1-3p is a hallmark of IgG4-DS. These miRNAs appear to be involved in the pathogenesis of IgG4-DS.

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD+ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by elevated IgG4 serum levels, abundant IgG4-positive plasmacyte infiltration, and fibrosis of various organs, including the head and neck. We aimed to provide an overall review of IgG4-RD in the sinonasal region and propose a novel entity and criteria of chronic rhinosinusitis (CRS) associated with IgG4-RD as "IgG4-CRS," a distinct manifestation of IgG4-RD in the sinonasal region. Sinonasal involvement has been increasingly recognized; however, this region is not included in the classic IgG4-RD-affected organs. The clinical features of IgG4-CRS, including its prevalence and relationship with allergies and olfactory disturbances, have also been explored. Serum IgG4 levels and IgG4-positive plasma cell infiltrations, crucial diagnostic factors, have been discussed in association with IgG4-CRS pathogenesis. Fibrosis, a hallmark of IgG4-RD, is observed in sinonasal tissues; however, typical fibrosis, such as storiform fibrosis, is not usually found. Mimics or complications in eosinophilic CRS (ECRS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are highlighted. Treatment often involves typically effective glucocorticoids. Organ-specific diagnostic criteria for the sinonasal region have not currently been established. Hence, this review aims to foster awareness and understanding of IgG4-CRS among ENT physicians and to provide a basis for future research and diagnostic refinement.

The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4+ cTfh cells were significantly decreased and the percentage of IFN-γ+ cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR.