Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis

Abstract

Depletion of the memory B-cell compartment contributes to the immunosuppression induced by sepsis. Therapies targeted at reversing this immune memory depletion warrant further investigation.

Can Concurrent Abnormalities in Free Light Chains and Immunoglobulin Concentrations Identify a Target Population for Immunoglobulin Trials in Sepsis?*

“…The roles in sepsis pathology and as a putative biomarker for IVIg therapy warrants further study. (14). High FLC in sepsis could be related to either excess production related to sepsis related inflammation or due to allelic inclusion of light chains in B cells (13,15).…”

“…Exclusion criteria included patients <18 years, those with congenital hypogammaglobulinemia, known protein-losing enteropathies, nephrotic syndrome, neoplastic or proliferative hematologic diseases; those having received IVIg therapy in the last 3 months; those receiving high-dose corticosteroid therapy; ongoing blood loss (defined by blood transfusion requirement > 2 units/24 hour period); retroviral disease; and immune dysfunction as defined by Acute Physiology and Chronic Health Evaluation (APACHE) II score co-morbidities (17). We have recently published other details on B cell changes in sepsis from this population, using the same cohort (14).…”

“…In health, excess light chains are present in the perinuclear space to prevent intracellular heavy chain aggregation prior to immunoglobulin assembly, and are secreted as FLC after immunoglobulin assembly (13). Thus, impaired immunoglobulin assembly in sepsis could result in raised FLC and low immunoglobulin levels (2,3,14). We also considered whether an altered stoichiometry of light chain production could contribute to raised FLC concentrations.…”

Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction

“…The regulatory T cells (Treg), an important T CD4+ T cell subset with immunosuppressive properties, are relatively preserved in sepsis. Total B cell counts are decreased with exaggerated loss of memory B cell subsets despite normal B cell-specific survival factor levels [19], with evidence of B cell exhaustion and increased proportions of regulatory B cells [8]. Preliminary results from an animal model highlight that the antibody-independent effect of B cells on the immune system such as granulocyte-monocyte colony-stimulating factor secretion [16] and cytokine secretion [12] may be relevant in sepsis biology, which require further investigation.…”

Intravenous immunoglobulin in sepsis: can we find the right dose?

“…B-cell apoptosis appears to be greater in memory cells when compared with naive B cells. This suggests that B-cell depletion is not a consequence of impaired bone marrow production 11 . Similarly to the CIGMA investigators and others, we have also found that the combined presence of low levels of the endogenous immunoglobulins IgG1, IgM and IgA in plasma is associated with reduced survival in patients with sepsis and multi-organ failure and the low IgM levels correlated with the high CRP values (courtesy of Dr Heurich-Sevchenko, unpublished data) 4,12 .…”