Academic Journal
Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency.
| Title: | Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency. |
|---|---|
| Authors: | Kowalczyk P; 3P-Medicine Laboratory, Medical University of Gdansk, 7 Dębinki st, Gdansk, 80-211, Poland. kowalczyk.paulina@gumed.edu.pl., Zima K; Department of Physiology, Medical University of Gdansk, 1 Debinki st, Gdansk, 80-211, Poland., Sowa-Rogozińska N; Department of Physiology, Medical University of Gdansk, 1 Debinki st, Gdansk, 80-211, Poland., Majewska-Szczepanik M; Chair of Biomedical Sciences, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 12 Michalowskiego st., Cracow, 33-332, Poland., Ziętkiewicz M; Department of Rheumatology, Clinical Immunology, Geriatrics and Internal Medicine, Medical University of Gdansk, 7 Dębinki st, Gdansk, 80-211, Poland. marcin.zietkiewicz@gumed.edu.pl. |
| Source: | Clinical reviews in allergy & immunology [Clin Rev Allergy Immunol] 2026 Aug 28; Vol. 69 (1). Date of Electronic Publication: 2026 Aug 28. |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: Humana Press Country of Publication: United States NLM ID: 9504368 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-0267 (Electronic) Linking ISSN: 10800549 NLM ISO Abbreviation: Clin Rev Allergy Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Totowa, NJ : Humana Press, c1995- |
| MeSH Terms: | Common Variable Immunodeficiency*/immunology , Common Variable Immunodeficiency*/metabolism , B-Lymphocytes*/immunology , B-Lymphocytes*/metabolism , T-Lymphocytes*/immunology , T-Lymphocytes*/metabolism , Immunity, Innate* , Autoimmunity*, Cytokines/metabolism ; Humans ; Animals ; Signal Transduction |
| Abstract: | Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, affecting approximately 1 in 25 000-50 000 individuals. Although classically characterized by hypogammaglobulinemia and recurrent bacterial infections, over 50% of patients develop non-infectious complications that constitute the major determinants of morbidity and mortality. The coexistence of immunodeficiency and immune dysregulation challenges the traditional B-cell-centric model of CVID pathogenesis. In this narrative review, we synthesize current evidence demonstrating that autoimmune manifestations in CVID arise from complex, multilayered immune dysfunction extending far beyond the B-cell compartment. Key abnormalities include Th1-skewed CD4⁺ T-cell responses with persistent IFN-γ production, numerical and functional defects in regulatory T cells, disruption of follicular T-cell subset balance favoring autoreactive germinal center responses, and progressive CD8⁺ T-cell exhaustion. At the innate immune level, NK-cell lymphopenia, constitutive monocyte activation, dendritic cell deficiency, neutrophil dysregulation, and proinflammatory innate lymphoid cell activity collectively contribute to the breakdown of self-tolerance. These immune perturbations are further amplified by systemic cytokine dysregulation. Pathogenic variants identified in patients with CVID-like disorders may further underlie autoimmune pathology and immune dysregulation, particularly those affecting T-cell co-stimulation, immune checkpoint signaling, NF-κB, and PI3K pathways. Collectively, CVID-associated autoimmunity represents a paradigm of systems-level immune dysregulation, underscoring the need for comprehensive immune phenotyping, genotype-informed stratification, and precision immunomodulatory strategies targeting the full spectrum of immune abnormalities involved. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Competing interests: The authors declare no competing interests. |
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| Contributed Indexing: | Keywords: Autoimmunity; Common variable immunodeficiency; Innate cells; T cells |
| Substance Nomenclature: | 0 (Cytokines) |
| Entry Date(s): | Date Created: 20260828 Date Completed: 20260828 Latest Revision: 20260831 |
| Update Code: | 20260831 |
| PubMed Central ID: | PMC13525027 |
| DOI: | 10.1007/s12016-026-09197-9 |
| PMID: | 42663782 |
| Database: | MEDLINE |
| ISSN: | 1559-0267 |
|---|---|
| DOI: | 10.1007/s12016-026-09197-9 |