ADHESION OF RHEUMATOID LYMPHOCYTES TO MUCOSAL ENDOTHELIUM: THE GUT REVISITED

By a study of the adhesion of rheumatoid mononuclear cells,we have sought to clarify the homing properties and originsof cells likely to be involved in the pathogenesis of this disease.The adhesion of mononuclear cells from patients with rheumatoidarthritis (RA) was enumerated by an in vitro adherence assayusing frozen sections of endothelium-containing gut lamina propria(EGLP) from porcine small intestine. Preliminary studies verifiedthe involvement of known adhesion molecules by inhibition assaysusing monoclonal antibodies Meca-367, Mel-14 and Hermes-3. Twenty-fivepaired samples of peripheral blood (PB) and synovial fluid (SF)were studied, plus six from synovial membrane (SM) and eightfrom patients with other diseases. There was a significantlygreater degree of adherence to EGLP by SF cells than PB (meanadherence 266 ± 22 cells/mm², compared to 136 ±13 cells/mm², respectively, the majority of which were CD8+cells; P = 0.02, Mann-Whitney U-test for 25 paired samples).The results of the monoclonal antibody inhibition assays werein keeping with the involvement of homing receptors to gut endotheliumin our assay system. Synovial fluid lymphocytes from RA patientsexhibited adhesion properties more in keeping with lymphocytesof mucosal than of lymph node origin. Synovial membrane lymphocytes,by contrast, showed poor adherence to endothelium-containinglamina propria. The gut, as an immune lymphoid organ, may thusplay a contributory role in this disease, possibly through thepathological seeding of cells into the synovial space. KEY WORDS: Rheumatoid arthritis, Adhesion, MALT     

Invasive Streptococcus pneumoniae trigger platelet activation via Toll‐like receptor 2

Summary. Background: Sepsis is the most common manifestation of invasive pneumococcal disease and is characterized by a severe systemic inflammatory state that leads to circulatory compromise or end organ malperfusion or dysfunction. Patients suffering from sepsis often display low platelet counts characterized by thrombocytopenia as a result of platelet activation. Objective: To investigate the mechanism through which platelets become activated in sepsis upon binding to Streptococcus pneumoniae. Patients and methods: We determined S. pneumoniae inducible platelet reactivity using light transmission aggregometry. Dense granule secretion was measured by luminometry using a luciferin/luciferase assay . Results : Streptococcus pneumoniae induced platelet aggregation in a strain‐dependent manner. Induction of aggregation was not attributable to capsule serotype, as unencapsulated strains also induced platelet aggregation. Platelet aggregation was not associated with pneumolysin toxin, as a pneumolysin‐deficient mutant of S. pneumoniae induced aggregation equally as well as the parent strain. Platelet aggregation also occurred in the absence of plasma proteins or antibody, and was GPIIbIIIa dependent but aspirin independent. Toll‐like receptor 2 (TLR2) is present on platelets and acts as a receptor for gram‐positive bacterial lipoteichoic acid and peptidoglycan. Inhibition of TLR2 but not TLR4 (also present on platelets) completely abolished platelet aggregation. S. pneumoniae‐induced platelet aggregation resulted in activation of the PI3kinase/RAP1 pathway, leading to integrin GPIIbIIIa activation and dense granule release. Conclusions : Our results demonstrate a novel interaction between S. pneumoniae and TLR2, which results in platelet activation that is likely to contribute to the thrombotic complications of sepsis.