Release of platelet-activating factor (PAF-acether) and arachidonic acid metabolites from alveolar macrophages

Human, monkey and rat alveolar macrophages (AM) release PAF-acether in a dose-dependent fashion in the presence of 1 to 5 g/ml ionophore A 23187 (2.5 pmol of PAF-acether from 2.5×10⁵ cells) but not in the presence of zymosan. Arachidonic acid (AA) metabolites released from AM from these species were studied. Thromboxane A₂ TxA₂)—detected by its action on rabbit arteries—was released from human, monkey and rat AM upon addition of 0.5 mM AA. This release was inhibited by aspirin and indomethacin. Lipoxygenase and cyclooxygenase AA metabolites from rat AM were identified using high efficiency glass capillary column gas chromatography coupled to mass spectrometry. The cyclooxygenase metabolites PGF₂, E₂ and D₂ and TxB₂ were identified. The lipoxygenase-dependent AA metabolites were explored using aspirin-pretreated AM. Only 12 HETE was found.These data indicate that AM secrete several substances with bronchoconstrictive activity: PGF₂, D₂, TxA₂ and PAF-acether. Therefore an active role of AM in human and experimental bronchoconstriction must be considered.     

Deletion of a coordinate regulator of type 2 cytokine expression in mice

Mechanisms that underlie the patterning of cytokine expression in T helper (T(H)) cell subsets remain incompletely defined. An evolutionarily conserved approximately 400-bp noncoding sequence in the intergenic region between the genes Il4 and Il13, designated conserved noncoding sequence 1 (CNS-1), was deleted in mice. The capacity to develop T(H)2 cells was compromised in vitro and in vivo in the absence of CNS-1. Despite the profound effect in T cells, mast cells from CNS-1(-/-) mice maintained their capacity to produce interleukin 4. A T cell-specific element critical for the optimal expression of type 2 cytokines may represent the evolution of a regulatory sequence exploited by adaptive immunity.     

Changes in immunoregulatory lymphocyte populations in patients with histoplasmosis

Circulating T-lymphocyte subpopulations were enumerated in 65 patients with histoplasmosis and correlated with the different clinical manifestations of the disease. Acute pulmonary histoplasmosis, rheumatologic, disseminated, and chronic inflammatory manifestations of histoplasmosis were all associated with a significant elevation above normal of OKT₈+ (suppressor-cytotoxic) lymphocytes and a significantly lower than normal OKT₄+ (helper-inducer)-lymphocyte to OKT₈+-lymphocyte ratio. In contrast, cavitary disease was associated with an increase in OKT₄+ lymphocytes, a decrease in OKT₈+ lymphocytes, and a higher than normal OKT₄/OKT₈ ratio. Clinical recovery was associated with normalization of these values. Functional activity determined by coculture techniques correlated closely with T-lymphocyte subset measurements. These distinct subset abnormalities may help monitor immunological aspects of disease activity.     

The protective effects of hyperimmune anti-murine cytomegalovirus antiserum against lethal viral challenge: the case for passive-active immunization

The administration of 0.2 ml of hyperimmune anti-mouse cytomegalovirus (CMV) antiserum intraperitoneally (ip) or intravenously provided complete protection against lethal challenge (10(5.8) PFU ip) with murine CMV. Antiserum protection was complete when the antiserum was administered as long as 24 hr after viral challenge. The administration of antiserum had little effect on the titers of virus in the organs of these animals. Ammonium sulfate-treated antiserum provided similar complete protection. Animals rechallenged with 10(6)-10(6.5) PFU of murine CMV 1 month after initial challenge, at a time when the administrated antiserum was no longer detectable, all survived. We conclude that hyperimmune antiserum can provide significant protection against otherwise lethal murine CMV infection, that the protecting material lies within the immunoglobulin fraction, and that long-term immunity results from the combined exposure to virus and antiserum. Such passive-active protection could be useful in protecting against human CMV infection.     

Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene

Serum calcium is under tight physiological control, but it is also a quantitative trait with substantial genetic regulation. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia or autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, ligand binding to the receptor protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor. We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15.4%. Mean total serum calcium (Ca(T)) was significantly higher in the SS (9.88 +/- 0.29 mg/dL, P = 0.015) and AS groups (9.45 +/- 0.05 mg/dL, P = 0.002), than in the AA group (9.23 +/- 0.04 mg/dL). In multiple regression modeling, the A986S genotype remained an independently significant predictor of Ca(T) (P < 0.0001) when serum albumin, globulin, inorganic phosphate, and creatinine covariates were included. These data are the first to show significant association between a common polymorphism and concentrations of a serum electrolyte. The A986S polymorphism is also a potential predisposing factor in disorders of bone and mineral metabolism.     

Molecular Insights into the Histogenesis and Pathogenesis of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) have long been problematic in terms of classification and determination of prognosis. Recent studies have suggested that GISTs differentiate toward a phenotype resembling the interstitial cells of Cajal. This has led to the important discovery that activating mutations in the KIT receptor tyrosine kinase play an important role in the pathogenesis of GISTs. These findings have helped clarify the distinction between GISTs and other mesenchymal neoplasms of the gastrointestinal tract and may translate into an improved ability to predict biologic behavior, as well as suggesting possible avenues for rational drug design for the treatment of GISTs. Int J Surg Pathol 8(1):5-10, 2000