Enhanced secretion of leukocyte‐associated immunoglobulin‐like receptor 2 (LAIR‐2) and soluble LAIR‐1 in rheumatoid arthritis: LAIR‐2 is a more efficient antagonist of the LAIR‐1–collagen inhibitory interaction than is soluble LAIR‐1

Objective

Human leukocyte‐associated immunoglobulin‐like receptor 1 (hLAIR‐1) is an immune inhibitory receptor for collagen that is expressed on most immune cells. We previously showed that the LAIR‐1–collagen interaction could be antagonized by the secreted homolog hLAIR‐2, which can be detected in the synovial fluid of rheumatoid arthritis (RA) patients. In addition, the extracellular part of hLAIR‐1 is a putative antagonist upon shedding from the cell membrane. The purpose of this study was to determine the relative roles of hLAIR‐2 and soluble hLAIR‐1 (shLAIR‐1) in the regulation of the LAIR‐1–collagen interaction.

Methods

The ability of recombinant LAIR proteins to abrogate LAIR‐1–collagen binding was tested by flow cytometry and adhesion assays. Collagen binding capacity was analyzed by surface plasmon resonance. Plasma, urine, and synovial fluid were screened for the presence of sLAIR‐1 and LAIR‐2 by enzyme‐linked immunosorbent assay.

Results

Recombinant LAIR‐2 proteins abrogated the binding of collagen to LAIR‐1 more efficiently than did recombinant sLAIR‐1. Consistent with these findings, surface plasmon resonance analysis showed that LAIR‐2 had a higher affinity for collagen than did LAIR‐1. Activated CD4+ T cells were the main producers of LAIR‐2, whereas the source of sLAIR‐1 remains elusive. Both soluble LAIR‐1 and LAIR‐2 could be detected in the plasma and urine of healthy control subjects and patients with RA. Urinary levels of both proteins were significantly increased in RA patients, and LAIR‐2 levels in urine were significantly correlated with markers of inflammation.

Conclusion

Our data suggest that LAIR‐2 is a more potent antagonist of LAIR‐1 function in vivo, while both sLAIR‐1 and LAIR‐2 are potential biomarkers that may be used to monitor urine samples for evidence of systemic inflammation.

     

Surgical excision of CNS‐draining lymph nodes reduces relapse severity in chronic‐relapsing experimental autoimmune encephalomyelitis

Despite lack of classical lymphatic vessels in the central nervous system (CNS), cells and antigens do reach the CNS‐draining lymph nodes. These lymph nodes are specialized to mediate mucosal immune tolerance, but can also generate T‐ and B‐cell immunity. Their role in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) therefore remains elusive. We hypothesized that drainage of CNS antigens to the CNS‐draining lymph nodes is vital for the recurrent episodes of CNS inflammation. To test this, we surgically removed the superficial cervical lymph nodes, deep cervical lymph nodes, and the lumbar lymph nodes prior to disease induction in three mouse EAE models, representing acute, chronic, and chronic‐relapsing EAE. Excision of the CNS‐draining lymph nodes in chronic‐relapsing EAE reduced and delayed the relapse burden and EAE pathology within the spinal cord, which suggests initiation of CNS antigen‐specific immune responses within the CNS‐draining lymph nodes. Indeed, superficial cervical lymph nodes from EAE‐affected mice demonstrated proliferation against the immunizing peptide, and the deep cervical lymph nodes, lumbar lymph nodes, and spleen demonstrated additional proliferation against other myelin antigen epitopes. This indicates that intermolecular epitope spreading occurs and that CNS antigen‐specific immune responses are differentially generated within the different CNS‐draining lymphoid organs. Proliferation of splenocytes from lymphadenectomized and sham‐operated mice against the immunizing peptide was similar. These data suggest a role for CNS‐draining lymph nodes in the induction of detrimental immune responses in EAE relapses, and conclusively demonstrate that the tolerance‐inducing capability of cervical lymph nodes is not involved in EAE. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The Effect of a Computerized Prescribing and Calculating System on Hypo‐ and Hyperglycemias and on Prescribing Time Efficiency in Neonatal Intensive Care Patients

Background: Prescribing glucose requires complex calculations because glucose is present in parenteral and enteral nutrition and drug vehicles, making it error prone and contributing to the burden of prescribing errors. Objective: Evaluation of the impact of a computerized physician order entry (CPOE) system with clinical decision support (CDS) for glucose control in neonatal intensive care patients (NICU) focusing on hypo‐ and hyperglycemic episodes and prescribing time efficiency. Methods: An interrupted time‐series design to examine the effect of CPOE on hypo‐ and hyperglycemias and a crossover simulation study to examine the influence of CPOE on prescribing time efficiency. NICU patients at risk for glucose imbalance hospitalized at the University Medical Center Utrecht during 2001–2007 were selected. The risks of hypo‐ and hyperglycemias were expressed as incidences per 100 patient days in consecutive 3‐month intervals during 3 years before and after CPOE implementation. To assess prescribing time efficiency, time needed to calculate glucose intake with and without CPOE was measured. Results: No significant difference was found between pre‐ and post‐CPOE mean incidences of hypo‐ and hyperglycemias per 100 hospital days of neonates at risk in every 3‐month period (hypoglycemias, 4.0 [95% confidence interval, 3.2–4.8] pre‐CPOE and 3.1 [2.7–3.5] post‐CPOE, P = .88; hyperglycemias, 6.0 [4.3–7.7] pre‐CPOE and 5.0 [3.7–6.3] post‐CPOE, P = .75). CPOE led to a significant time reduction of 16% (1.3 [0.3–2.3] minutes) for simple and 60% (8.6 [5.1–12.1] minutes) for complex calculations. Conclusions: CPOE including a special CDS tool preserved accuracy for calculation and control of glucose intake and increased prescribing time efficiency.     

Successful clozapine continuation during chemotherapy for the treatment of malignancy: a case report

Case

The need for chemotherapy treatment in a cancer patient who uses clozapine raises a clinical dilemma because both therapies can cause agranulocytosis. A 45-year-old male diagnosed with schizophrenia used clozapine together with zuclopenthixol for more than 15 years. Non-Hodgkin’s lymphoma was treated with chemotherapy twice, and clozapine was continued during both courses of chemotherapy. Agranulocytosis did not occur during the first treatment. During the second treatment, agranulocytosis occurred, but was attributed to chemotherapy, and blood counts recovered spontaneously. Successful concomitant use of clozapine and cancer chemotherapy is based on a limited number of case reports. However, two case reports describe persistent neutropenia or agranulocytosis, possibly related to this combination.

Conclusion

Clozapine should only be continued during cancer chemotherapy if favoured by the risk-to-benefit ratio.