Mechanistic Insights Into Immune Cell Dysregulation Mediated by Novel Heterozygous Variants in CARD11 and MALT1.

Dysregulation of the CARD11-BCL10-MALT1 (CBM) complex is associated with a group of inborn errors of immunity termed “CBM-opathies,” which encompass a spectrum of clinical manifestations including combined immunodeficiency, autoimmune inflammation, atopic disorders, and lymphoproliferation. In this study, we identified novel compound heterozygous variants in the CBM complex in a patient with a family history of immune dysfunction. The patient inherited the variants CARD11 p.K215N and MALT1 p.K543R/p.M732T from asymptomatic carrier parents. Phenotypically, the patient exhibited a developmental arrest of B lymphocytes at the transitional/naïve B cell stage, accompanied by activation of virus-response pathways. Impaired development of T follicular helper cells was linked to defective germinal center formation and agammaglobulinemia. Furthermore, the patient showed expansion of T peripheral helper cells and a deficiency in regulatory T cells, both associated with autoimmunity and colitis. In vitro studies confirmed an imbalance in Tph/Tfh cell differentiation. Single-cell RNA sequencing further revealed a deficiency in B cell development and an enriched population of pro-inflammatory CD3dimCD4−CD8−CD247+ T cells, functionally enriched in the MAPK signaling pathway. Mechanistically, the MALT1 K543R and M732T variants attenuated MALT1’s enzymatic activity and compromised its protein stability, while the CARD11K215N variant disrupted CARD11-mediated promotion of BCL10 filament formation. We demonstrated that these three variants act synergistically to impair NF-κB activation. Specifically, CARD11K215N cooperates with the co-pathogenic MALT1M732T and the modifier variant MALT1K543R to destabilize the functional integrity of the CBM complex, thereby driving the patient’s phenotype. In summary, our study provides new insights into the pathogenesis of autoimmune inflammatory disorders within the spectrum of CBM-opathies and reveals a potential role for the CBM complex in regulating the balance between T peripheral helper and T follicular helper cells.