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This research received no external funding. K.G.-H is supported by The European Social Fund (ESF) through a Río Ortega Grant for Health Research Projects by the Carlos III Health Institute (ISCIII) (CM20/00098)., B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities., Depto. de Inmunología, Oftalmología y ORL, Fac. de Medicina, TRUE, pub

La inmunodeficiencia secundaria (IDS) a malignidad hematológica (MH) representa un problema de salud y un reto importante debido a la alta tasa de morbimortalidad asociada a infecciones recurrentes y graves en estos pacientes, siendo el prototipo de IDS la leucemia linfática crónica (LLC) y el mieloma múltiple (MM). En 1980, se propuso la evaluación de producción de anticuerpos específicos, polisacáridos – tras vacunación antineumocócica 23-valente (PPV-23) y proteicos - tras vacunación anti-tetánica (TT) u otras -, como predictor del riesgo de infección y, por tanto, como guía para la indicación de la terapia sustitutiva con inmunoglobulinas (TSIg). Sin embargo, ha sido en 2019 que la Agencia Europea del Medicamento (EMEA) ha introducido esta evaluación del déficit de producción de anticuerpos como criterio del inicio de la TSIg, abriendo la indicación a cualquier paciente con IDS, que incluye otras MH como el linfoma no Hodgkin (LNH) o la gammapatía de significado incierto (GMSI). Debido a la complejidad de la interpretación de la respuesta vacunal específica frente a polisacárido neumocócico tras la introducción de la vacuna antineumocócica conjugada 13-valente (PCV-13) en el esquema de inmunización, nuestro grupo y diversos autores han propuesto la evaluación de la respuesta de IgG específica frente al polisacárido puro de S. typhi (TV) como biomarcador de riesgo de infección complementario a PCV-13 y TT en inmunodeficiencia primaria (IDP)..., Secondary immunodeficiency (SID) due to hematological malignancy (HM) represents a health problem concern and an important challenge due to high rate of morbidity and mortality associated with recurrent and severe infections. Initial assessment of specific antibody (Ab) responses – after polysaccharide 23-valent pneumococcal (PPV-23) and tetanus toxoid (TT) protein vaccine- in HM was proposed in the 80's as a more reliable predictor of infections to start immunoglobulin replacement therapy (IgRT). Patients affected by hematological malignancy, in particular chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), were recognized as presenting Ab production deficits many years ago. However, it was not until 2019 when a new indication of the European Medicines Agency (EMA) has included the defect of specific Ab response as an indication for IgRT in SID with recurrent infections, allowing the inclusion of other HM patients, such as non-Hodgkin's lymphoma (NHL) or gammopathy of uncertain significance (MGUS). However, interpretation of pure polysaccharide 23-valent immunization is hampered by the high endemicity of pneumococcal disease and the generalization of the 13-valent adjuvant pneumococcal vaccination (PCV-13). Specific IgG anti-Salmonella typhi Ab response has been proposed as a biomarker of risk of infection complementary to PCV-13 and TT in primary immunodeficiency (PID)...

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.