F-actin remodeling defects as revealed in primary immunodeficiency disorders.

Primary immunodeficiencies (PIDs) are a heterogeneous group of immune-related diseases. PIDs develop due to defects in gene-products that have consequences to immune cell function. A number of PID-proteins is involved in the remodeling of filamentous actin (f-actin) to support the generation of a contact zone between the antigen-specific T cell and antigen presenting cell (APC): the immunological synapse (IS). IS formation is the first step towards T-cell activation and essential for clonal expansion and acquisition of effector function. We here evaluated PIDs in which aberrant f-actin-driven IS formation may contribute to the PID disease phenotypes as seen in patients. We review examples of such contributions to PID phenotypes from literature, and highlight cases in which PID-proteins were evaluated for a role in f-actin polymerization and IS formation. We conclude with the proposition that patient groups might benefit from stratifying them in distinct functional groups in regard to their f-actin remodeling phenotypes in lymphocytes.

Increased prevalence of gastrointestinal viruses and diminished secretory immunoglobulin a levels in antibody deficiencies.

PURPOSE: Gastrointestinal disease occurs frequently in antibody deficiencies. This study aims to explore the relation between gastrointestinal infections and mucosal homeostasis in patients with antibody deficiencies. METHODS: We performed an observational study including 54 pediatric antibody deficient patients (48 % CVID, 41 % CVID-like, 11 % XLA) and 66 healthy controls. Clinical symptom scores and stool samples were collected prospectively. Stool samples were evaluated for bacteria, parasites, viruses, secretory IgA- and for calprotectin levels. Results were compared between patients and controls. RESULTS: 24 % of antibody deficient patients versus 9 % of healthy controls tested positive for gastrointestinal viruses (p = 0.028). Fecal calprotectin levels were significantly higher in virus positive patients compared to virus negative patients (p = 0.002). However, in controls, fecal calprotectin levels were similar between virus positive and virus negative controls. Moreover, gastrointestinal virus positive patients had low serum IgA levels in 13/14 cases (94 %) versus 40/62 (62 %) patients in the virus negative patient group (p = 0.04). The virus positive patient group also displayed significantly lower secretory IgA levels in stool (median 13 ug/ml) than patients without gastrointestinal viruses detected or healthy controls (median 155 ug/ml) (p = 0.046). CONCLUSION: We here report an increased prevalence of gastrointestinal viruses and gastrointestinal complaints in antibody deficient patients. Patients that tested positive for gastrointestinal viruses showed diminished serum- and secretory IgA levels, and only in patients, virus positivity was associated with signs of mucosal inflammation. These findings suggest that particularly patients with low IgA are at risk for longstanding replication of gastrointestinal viruses, which may eventually result in CVID-related enteropathy.