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    • LY2584702 Another key point relates to the lower

    2018-11-07

    Another key point relates to the lower counts of CD4+ T cells, naïve CD4+ T cells and LY2584702 in the group of patients with severe NK cell lymphopenia. Indeed, severe CD4+ T cell deficiency and naïve CD4+ T cell deficiency have been associated with the “LOCID” phenotype, with a high frequency of non-infectious disease-related complications and opportunistic infections (Malphettes et al., 2009). Similarly, the “no-B” phenotype (B cells<1%) and the presence of dysregulated B-cell subpopulations (low proportions of switched memory B cells, high transitional and CD21low B cell counts) are associated with clinical complications, such as splenomegaly, lymphadenopathy and granuloma (Wehr et al., 2008). In this line, higher rates of invasive infections and non-infectious complications observed in patients with NK cell deficiency could be explained by global, T and B cell lymphopenia observed in these patients. Nevertheless, patients with the “no-B″ phenotype, severe CD4+ T cell deficiencies (<200×106/L) and very low naïve CD4+ T cell counts (<20×106/L) accounted for “only” 16.5%, 8.1% and 25.3%, respectively, of the patients with severe NK cell LY2584702 deficiency, suggesting that these factors alone cannot account for the observed phenotype of patients with severe NK cell lymphopenia. The persistence of a higher frequency of pneumonia and bacteremia in the T+NK− subgroup also suggests that NK cells could contribute to this phenotype. Although the coexistence of T cell and B cell deficiencies associated in these patients introduce some difficulties in interpreting the clinical manifestations observed, we are convinced that it is in these “non-redundant” conditions of associated adaptive immune system deficiency that NK cell deficiency could be clinically relevant. Unfortunately, to show strictly and statistically this point, comparison should be performed between T−(B−)NK− and T−(B−)NK+ groups, but these groups are the smallest groups (most uncommon patients) within our large cohort of CVID patients, with only respectively 8 and 18 patients. These numbers do not enable us to make stringent statistical analysis on the independent role of NK cells. Finally, the coexistence of T, B and NK cell deficiencies in some patients with CVID raises questions about the possibility of an as yet unidentified genetic defects leading to global lymphopoietic deficiencies in at least some of these patients (Ochs, 2014). Mortality was not significantly higher in patients with severe NK cell deficiency than in patients with mild or no NK cell deficiency in our study. Nevertheless, mortality was particularly high (41.7% at 5years) in the subgroup of patients with both severe NK cell lymphopenia and a severe CD4+ T cell deficiency. This suggests that NK cells could play a non-redundant role when the adaptive immune system, and the CD4 compartment in particular, is not optimal. Another recent study in 40 patients with idiopathic CD4 lymphopenia reported similar conclusions, with a correlation between low peripheral NK cell counts, and a high frequency of infections and low survival in these patients (Régent et al., 2014). In the same line, a recent study in five unrelated children with inherited DOCK2 deficiency, leading to T-cell, B-cell, and NK-cell defective responses, found early-onset invasive bacterial infections in these patients (Dobbs et al., 2015). In conclusion, this large cohort study of CVID patients, despite some limitations, provides new insight into the functions of NK cells in vivo. Patients with CVID and NK cell deficiency seem to have a particular phenotype, with high frequencies of severe bacterial infections (pneumonia and bacteremia), and non-infectious disease-related complications, such as granuloma in particular. These data suggest that we should reconsider the role of human NK cells in controlling non-viral infections, such as extracellular bacterial infections in particular. The high frequency of these pathological events in this group of patients, and the high mortality of the T−NK− subgroup suggest that NK cells may have non-redundant immune functions in humans when the adaptive immune response is not optimal, and that reciprocally NK cells exert redundant functions in natura in normal individuals, at least in adults. This observation and the absence of a specific phenotype in SCID patients displaying a failure to reconstitute the NK compartment after HSCT suggest that there may be cooperation between T cells and NK cells, with NK cells helping to protect against pathogenic bacteria in the absence of T cells but becoming redundant if T cells are present. Several advantages are associated with redundant mechanisms. First, they can provide robust fail-safe mechanisms that ensure adequate protection (Nish and Medzhitov, 2011). Second, they can also limit the risk of immunopathologies, by ensuring the limited activation of each lymphocyte subset on challenge (Nish and Medzhitov, 2011). Our results thus pave the way for dissecting in more detail the interplay between NK cells, T cells and B cells in the control of bacterial infections in natura.