This study aimed to depict the panorama of PIDs including clinical features, immune profiles and associated autoimmune phenomenon, focusing especially on CVID and SIgAD. 

We performed a retrospective analysis in a single-center cohort of 381 patients with PIDs, and summarized their genetic mutations and AID manifestations. CVID (159, 41.7%) and sIgAD (68, 17.8%) composed the main part of PIDs. Unsupervised K-means clustering based on peripheral blood lymphocyte subset distributions and immunoglobulin quantitation were used to define immunophenotypic subgroups in CVID and in SIgAD. Clinical features, genetic findings, and immune profiles were compared across clusters and between patients with and without autoimmunity.

AID was not rear in PIDs that a prevalence of 28.9% affecting 110 patients with various type of manifestations was observed. CVID and SIgAD exhibited distinct yet overlapping clinical and immunological characteristics. CVID patients were older at diagnosis (median 27.0 vs. 16.0 years, P < 0.001) and experienced longer diagnostic delays (21.0 vs. 5.0 months, P < 0.001) than SIgAD patients. CVID patients complicated with AIDs showed even lower serum IgA (median 0.01 g/L, P=0.02) and IgM levels (median 0.03 g/L, P=0.01), accompanied by reduced B-cell proportions (median 0.40%, P=0.04). Unsupervised clustering identified three CVID subgroups: Cluster Ⅰ (n=91), characterized by severe lymphopenia and hypogammaglobulinemia and susceptibility to AIDs; Cluster Ⅱ (n=47), marked by CD8+ T-cell activation (CD8+DR+/CD8+, 60.83±23.74, P=0.02; and CD8+CD28+/CD8+, 24.95±16.08, P<0.001); and Cluster Ⅲ(n=21), exhibiting a relatively preserved immune profile.

In SIgAD, clustering distinguished a subgroup prone to localized infections (Cluster I, n=19) with less T/B cells (CD3+T cell, 1073.36±530.96 vs. 2009.30±766.53 mm⁻³, P<0.001; and B cell, median 150 vs. 470 mm⁻³, P<0.001) and a subgroup with increased AID prevalence (Cluster III, n=29; 58.6% vs. 26.3%, P=0.028). AIDs were enriched in a SIgAD subgroup characterized by severe IgA deficiency (median 0.04 vs. 0.07 g/L, P=0.038), higher B-cell counts (median 434.5 vs. 210 mm⁻³, P=0.048), and higher CD4⁺/CD8⁺ T-cell ratio (median 1.37 vs. 1.05, P=0.02).

Distinct immunophenotypic subgroups in CVID and SIgAD are associated with differential risks of infection and autoimmunity, supporting immune dysregulation as a central driver of disease heterogeneity, and highlighting the clinical utility of immune profiling for risk stratification in PIDs.