Granulomatous-lymphocytic interstitial lung disease (GLILD) develops in 10–30% of patients with common variable immunodeficiency (CVID) as a consequence of immune dysregulation. Therefore, immunoglobulin (Ig) M, produced by apoptosis-resistant plasmablasts in extrafollicular sites in the lungs, and serum soluble interleukin-2 receptor (sIL-2R), shed by activated T lymphocytes, can both be elevated. The aim of this study was to evaluate whether these biomarkers are associated with higher risk of GLILD development.
A retrospective single-center case-control study was conducted comparing CVID patients with GLILD (n = 9) and without GLILD (n = 13). Concentrations of IgM (normal/elevated normal vs. low/undetectable) were compared between the groups using Fisher’s exact test. Due to technical limitations, the concentration of sIL-2R was measured only in several patients.
No statistically significant association was found between GLILD and IgM concentration (normal/elevated normal vs. low/undetectable) (p = 0.66), although patients with normal/elevated normal IgM levels had twofold higher odds of having GLILD (odds ratio [OR] 2; 95% confidence interval [CI] 0.36–11.2). The wide CI suggests the main limitation of our study: the small sample size (22 CVID patients in total). Preliminary data also showed that sIL-2R concentrations were significantly elevated in patients with GLILD (mean 1,059 IU/mL, normal <350 IU/mL).
Even though statistical significance was not shown, the results illustrate that elevated IgM levels may be associated with an increased risk of GLILD, suggesting a potential role for IgM in disease pathogenesis. Furthermore, higher sIL-2R levels reinforce the concept of immune dysregulation as a key feature of this CVID phenotype. Larger, multicenter studies with greater sample sizes are needed to clarify this potential association. If confirmed, longitudinal monitoring of these biomarkers could contribute to the earlier identification of CVID patients at higher risk of developing GLILD.
Aleksandra Dašić, Rada Mišković, S. Janković et al.· Journal of Human Immunity· 0 citations
22q11.2 deletion syndrome (22q11.2 DS) is one of the most common microdeletion syndromes, characterized by congenital anomalies and variable immune dysfunction secondary to thymic hypoplasia. The resulting immune dysregulation frequently predisposes affected individuals to autoimmune manifestations, including immune thrombocytopenia (ITP). Although rituximab is established therapy for refractory ITP, its B cell–depleting mechanism may carry distinct risk in patients whose B cell compartment already depends on impaired T cell–mediated help, potentially resulting in profound and irreversible humoral failure rather than the typically transient hypogammaglobulinemia.
We report the case of a female patient whose initial clinical manifestations included characteristic facial dysmorphism, cleft palate, a hemodynamically significant ventricular septal defect requiring surgical correction at the age of three years, and delayed psychomotor development. Based on these findings, 22q11.2 DS was suspected and subsequently confirmed by fluorescence in situ hybridization (FISH) analysis at the age of nine. At the age of five, she developed severe ITP, refractory to glucocorticoids, intravenous immunoglobulins, and cyclosporine. Immunophenotyping of peripheral blood lymphocytes at this stage already revealed reduced B cell counts (8%, 0.105 × 109/L), while serum IgG levels remained within the normal range. At the age of 12, she received rituximab therapy, achieving a complete normalization of platelet counts. Within the following year, she developed recurrent bilateral pneumonias. Laboratory evaluation revealed severe hypogammaglobulinemia (IgG 0.6 g/L, IgM 0.04 g/L, and IgA 0.06 g/L), with a further reduction in B cell numbers (4%, 0.066 × 109/L). Monthly intravenous immunoglobulin replacement therapy, combined with antibiotic prophylaxis, significantly reduced the frequency of infections. Hypogammaglobulinemia and B cell deficiency persisted without recovery over more than a decade of follow-up. At the age of 24 years, the patient developed severe COVID-19 pneumonia, which ultimately resulted in a fatal outcome.
This case highlights that rituximab, while effective in the treatment of autoimmune cytopenias, may induce severe and persistent hypogammaglobulinemia in patients with underlying primary immunodeficiency and pre-existing B cell abnormalities. Our patient’s humoral failure after rituximab proved persistent, a finding that may be attributable to an underlying thymic-dependent defect in B cell maturation, which could impair normal post-depletion recovery. Comprehensive baseline immunological evaluation and long-term monitoring of immunoglobulin levels and B cell recovery should be considered before B cell–depleting therapies in this population.
Ana Drazic, S. Pasic, Maja Stojanović et al.· Journal of Human Immunity· 0 citations
Inborn errors of immunity (IEIs) frequently present with rheumatologic and autoimmune manifestations that closely mimic common polygenic conditions, including systemic lupus erythematosus, juvenile idiopathic arthritis, and vasculitis, posing significant challenges to early recognition and diagnosis. Current data indicate that autoimmunity represents the first clinical manifestation in approximately 18% of IEI cases and the sole presentation in nearly 9%. The majority of affected patients belong to the categories of predominantly antibody deficiencies, combined immunodeficiencies with syndromic features, or disorders of immune dysregulation. In contrast to autoimmunity in the general population, IEI-associated autoimmunity characteristically presents at an earlier age, lacks a marked female predominance, and more frequently involves multiple organ systems, particularly hematopoietic, endocrine, and barrier tissues. Concurrently, the conceptual framework of autoimmunity is undergoing a fundamental shift: the classical model centered on central and peripheral tolerance is increasingly giving way to a pathway-oriented paradigm that foregrounds dominant immunologic mechanisms, including disturbances in T cell development, interferon signaling, and complement regulation. In line with this, a novel multilayer model of autoimmunity has recently been proposed, which integrates causative genes, the functional consequence of allelic variants (loss-of-function, gain-of-function, hypomorphic, haploinsufficient, or dominant-negative), disrupted molecular mechanisms, and their humoral and cellular immune effectors. A deeper understanding of these pathways is essential for enhancing diagnostic precision and for developing targeted, mechanism-based therapeutic strategies.
Rada Mišković· Journal of Human Immunity· 0 citations
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