Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+ T Lymphocytes in Humans

Abstract

Patients with sepsis have impaired host defenses that contribute to the lethality of the disorder. Recent work implicates lymphocyte apoptosis as a potential factor in the immunosuppression of sepsis. If lymphocyte apoptosis is an important mechanism, specific subsets of lymphocytes may be more vulnerable. A prospective study of lymphocyte cell typing and apoptosis was conducted in spleens from 27 patients with sepsis and 25 patients with trauma. Spleens from 16 critically ill nonseptic (3 prospective and 13 retrospective) patients were also evaluated. Immunohistochemical staining showed a caspase-9-mediated profound progressive loss of B and CD4 T helper cells in sepsis. Interestingly, sepsis did not decrease CD8 T or NK cells. Although there was no overall effect on lymphocytes from critically ill nonseptic patients (considered as a group), certain individual patients did exhibit significant loss of B and CD4 T cells. The loss of B and CD4 T cells in sepsis is especially significant because it occurs during life-threatening infection, a state in which massive lymphocyte clonal expansion should exist. Mitochondria-dependent lymphocyte apoptosis may contribute to the immunosuppression in sepsis by decreasing the number of immune effector cells. Similar loss of lymphocytes may be occurring in critically ill patients with other disorders.

Immunoparalysis and Adverse Outcomes from Critical Illness

“…Monneret and others have recently demonstrated associations between immunoparalysis and the subsequent development of a T reg -dominant adaptive immune response [55,56]. It has also been clearly shown in critically ill adults [57] and children [58] that lymphocyte apoptosis and lymphopenia are common in ICU nonsurvivors. The temporal and causal relationships between innate and adaptive immune dysfunction in critical illness remain incompletely understood.…”

Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure

“…Major findings in sepsis-induced immunosuppression include reduced monocytic phagocytotic activity, changes in monocytic cytokine expression profiles towards an anti-inflammatory phenotype (e.g. increased IL-10 expression), diminished monocytic antigen presentation via the major histocompatibility (MHC) class II complex [4], lymphocytic dysfunction and apoptosis-induced loss of circulating Tand B-lymphocytes [13]. In particular, a diminished surface expression of human leukocyte antigen (HLA)-DR molecules on monocytes (mHLA-DR) was proposed to serve as a sensitive (functional) surrogate index for sepsis-induced immunosuppression (reviewed in [4]).…”

Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection

“…In particular, nitric oxide (NO), a proximal mediator of the inflammatory cascade in sepsis, exerts inhibitory effects on mitochondrial electron transport chain complexes. Histopathologic evidence in splenic autopsies of septic patients suggests the mitochondrial pathway plays a prominent role in lymphocyte apoptosis [90]. Furthermore, skeletal muscle ATP concentrations were significantly lower in patients with sepsis who subsequently died than those who ultimately survived [108], a finding which could be correlated to overproduction of NO and depletion of cellular antioxidant capacity.…”

“…Lymphocyte populations depleted through apoptosis in septic patients include B cells and CD4 ? T cells [90]. Apoptotic loss of splenic follicular dendritic cells is also apparent, however, macrophages populations are notably preserved [94].…”

“…Coincident with this state of diminished immune function, autopsies of septic patients in adult, pediatric and neonatal age groups have revealed extensive apoptosis of splenic lymphocytes [90][91][92]. Lymphocyte apoptosis is also appreciated as an early event in peripheral blood of septic patients, with the degree of apoptosis correlating to the severity of sepsis symptoms, and profound and persistent lymphopenia a harbinger of poor outcome [93].…”