Bridging Primary Immunodeficiency and Rheumatic Disease: From Monogenic Prototypes to Multifactorial Autoimmunity

Primary immunodeficiencies (PIDs) and rheumatic diseases have long been considered distinct clinical entities, yet growing evidence reveals substantial overlaps in their pathogenic mechanisms. Monogenic immunodeficiencies, with their defined genetic defects, often present with striking rheumatic or autoinflammatory phenotypes, while advanced immunological and cytometric profiling, developed within the field of PIDs, is increasingly being applied to multifactorial rheumatic diseases. This intersection opens novel avenues for understanding disease mechanisms, discovering biomarkers, and developing targeted therapeutic approaches for both rare and common immune-mediated disorders.

This Research Topic aims to highlight the emerging interface between inborn errors of immunity and rheumatology, both at the genetic and clinical-phenotypic level. We seek to address how the detailed immunological and genetic work-up and techniques originally designed for PIDs can improve the classification, stratification, and treatment of multifactorial rheumatic diseases. The issue will explore:

• Monogenic mimics of rheumatic diseases and, conversely, autoantibody-mediated “secondary” mimics of immunodeficiencies (e.g., anti-cytokine autoantibodies, drug-induced phenomena);

• The clinical utility of advanced immune profiling and multi-omics in patients with suspected or established autoimmunity;

• The value of Mendelian prototypes of immune dysregulation (e.g., DADA2, CTLA4, STAT1/STAT3 GOF, immune actinopathies, interferonopathies, monogenic lupus) as models to dissect multifactorial autoimmunity and systemic inflammation.

• The dissection of novel genetic mechanisms responsible for incomplete disease penetrance or late-onset presentation in adults, such as aRMAE, somatic mosaicism, or interacting protein haplotypes (e.g., STING haplotypes in COPA syndrome).

We invite contributions on a broad range of related topics, including but not limited to:

• Clinical and molecular characterization of monogenic “mimics” of rheumatic disease

• Application of immunophenotyping and cytometric techniques in autoimmune and autoinflammatory disorders

• The role of autoantibody-mediated pathology simulating monogenic defects

• Insights from the study of somatic mosaicism, incomplete penetrance, and new genetic mechanisms in immune dysregulation

• Integration of biomarkers and omics strategies for patient stratification and tailored therapy

• Translational approaches applying knowledge from primary immunodeficiency to rheumatologic care and vice versa

We welcome Original Research, Reviews, Mini-reviews, Brief Research Reports, and Perspectives. Clinical cases will be considered only if highly innovative and thoughtfully contextualized with the existing literature.