Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis

Abstract

The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360-617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis.

A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense

“…On the other hand, integrins are required for host defense, demonstrated by the requirement for Mac-1 to clear bacteria 22 – 24 , 51 . Clinically, blood concentrations of soluble CD40L 52 and sCD18 53 are associated with sepsis, suggesting that both, Mac-1 and CD40L, participate in the acute inflammatory response in sepsis. To outweigh its conflicting effects on host defense and pathologic inflammation, we hypothesized that a ligand-specific blockade would be superior to an unspecific inhibition of Mac-1 in polymicrobial sepsis.…”

Structural Immunology of Complement Receptors 3 and 4

“…One important observation made, so far only by Gjelstrup et al is the oligomeric state of the sCD18 species ( 45 ). It is likely that the oligomerization enables a strong, polyvalent interaction with ligand-coated surfaces such as the tested surfaces with ICAM-1 ( 44 – 46 ) and iC3b ( 48 ). It was observed that recombinant sCR3 fragments oligomerize ( 49 ), but the relationship between these oligomers ( 45 ) with the oligomer forms found in plasma remains unclear.…”

Decreased monocyte shedding of the migration inhibitor soluble CD18 in alcoholic hepatitis

“…Further, disease remission in early rheumatoid arthritis is associated with increased sCD18 levels 26 . Finally, very high and very low levels of sCD18 levels were recently associated with fatal outcomes in critically ill sepsis patients 27 . Therefore, changes in sCD18 levels seems to be part of the inflammatory response in general.…”