Faculty Bibliography

It is often difficult to differentiate between an exacerbation of systemic lupus erythematosus (SLE) and intercurrent pre-eclampsia in a patient with SLE since the manifestations of both entities include proteinuria and hypertension. This study was undertaken to determine wether serum C3 and C4 values can help distinguish SLE activity from pre-eclampsia. In 21 nonpregnant women of child-bearing age, the mean C3 level was 124 +/- 5 mg/dl and the mean C4 was 31 +/- 1 mg/dl. In 24 normal women in the third trimester of pregnancy, the C3 and C4 levels were elevated (165 +/- 4 mg/dl, p less than 0.001 versus nonpregnant control women; 37 +/- 2 mg/dl, p less than 0.01 versus nonpregnant control women, respectively). In 17 women in the third trimester of pregnancy with documented pre-eclampsia, the mean C3 level was 162 +/- 4 mg/dl, no different from that in normal pregnant women (p less than 0.001 versus nonpregnant control women; p = NS versus normal pregnant women), and the mean C4 was 29 +/- 3 mg/dl, lower than that found in normal pregnant women (p less than 0.02 versus normal pregnant women). Antinuclear antibody was absent at titers of less than 1:20 in all of these pre-eclamptic patients. In contrast, pregnant women with SLE has significantly lower C3 (103 +/- 13 mg/dl) and C4 (15.3 +/- 3.6 mg/dl) values during the third trimester of pregnancy than either normal pregnant women (p less than 0.001 for C3 and C4) or women with pre-eclampsia (p less than 0.001 for C3 and p less than 0.004 for C4) during the third trimester of pregnancy. Of the eight women with SLE in whom serial complement values were determined, three had falling C3 or C4 levels, and in each, there was a flare of SLE activity either during or immediately after pregnancy. None of the five patients with a rising C3 concentration had a flare of disease activity; however, pre-eclampsia developed in one of these patients, characterized by hypertension and proteinuria. Thus, measurement of serum C3 and C4 can help differentiate between SLE activity and pre-eclampsia, since both C3 and C4 are significantly lower in women with SLE than women with pre-eclampsia, and serum C3 and C4 concentrations rise during uncomplicated or pre-eclamptic pregnancy in women with SLE.

Thirty-six patients with osteoid osteomas in the hip were retrospectively studied, including 30 with intraarticular nidi and six with extracapsular nidi. Osteoarthritis developed in 50% of those patients with intraarticular lesions; none of the patients with extracapsular lesions had joint changes. Rheumatologic studies were conducted with eight of the patients with osteoarthritis. The cause of the degenerative joint disease is open to speculation. However, as five of the eight patients had major histocompatibility (HLA) markers for rheumatoid arthritis, the presence of this HLA factor may indicate the patients at risk for inflammatory changes in the joint

Neonatal lupus syndromes consist of transient cutaneous and hematologic abnormalities and permanent cardiac disorders all of which result from a common pathogenetic mechanism, the passive transfer of maternal autoantibodies. Detrimental antibodies such as SSA/Ro and SSB/La gain access to the fetal circulation via the normal active transport system of the trophoblast tissue which is operative after 20 weeks gestation. Despite functional maturation of the cardiac conduction system by 16 weeks gestation, fetal bradycardias are most often encountered after this time. Several lines of evidence are advanced in this review to support the role of myocarditis as the initial consequence of autoantibody attack on the fetal heart. The end result of this inflammatory insult is permanent fibrosis manifest as complete congenital heart block (CCHB). Despite the clearly demonstrated presence of SSA/Ro and SSB/La in fetal tissues as well as their fluctuation in quantity during the cell cycle, the precise accessibility of these antigens to their respective autoantibodies in unknown at the present time. However, ultraviolet light is reported to induce cell surface expression of SSA/Ro on cultured keratinocytes. The recognition of CCHB by fetal echocardiogram is presented. The rationale for the use of dexamethasone which crosses the placenta in an active form to treat fetal immune effector functions is discussed. Intense maternal plasmapheresis in an attempt to rapidly decrease maternal autoantibodies may provide another approach to the management of CCHB. Through increasing knowledge of this model of "passively acquired pure" systemic lupus erythematosus, insights into mechanisms of tissue injury and strategies for treatment will emerge.

Neutrophils were preincubated with 17 beta-estradiol and progesterone to determine the effects of these hormones on chemotactic peptide-stimulated superoxide anion (O2-) generation and degranulation. At pharmacologic levels 17 beta-estradiol was more active than progesterone with respect to inhibition of O2- generation as well as degranulation. An increase of preincubation time from 5 minutes to 25 minutes increased the percent inhibition. When 17 beta-estradiol and progesterone were combined at levels which approximate those measured during gestation, there was small but significant inhibition of O2- generation. Dexamethasone at equal molar concentration inhibited O2- generation only after 25 minutes of preincubation and at no time reached the level of inhibition attained by either of the sex hormones alone. Both estradiol and progesterone at pharmacologic levels significantly inhibited beta-glucuronidase and lysozyme release, whereas dexamethasone did not inhibit degranulation despite prolonged preincubation. Neutrophils isolated from women during various phases of the menstrual cycle and during the third trimester of pregnancy did not differ with respect to chemotactic peptide-stimulated O2- generation. These data suggest that inhibition of neutrophil responses requires the continuous presence of pharmacologic levels of estradiol and progesterone

Neutrophils respond to a variety of stimuli by generating superoxide anion, degranulating, and aggregating. Because it has been suggested that fusion of granules with the plasmalemma (degranulation) is necessary for aggregation and superoxide anion generation, we have tested whether these responses can be demonstrated in 'neutrophilic cytoplasts' (granule-free vesicles of cytoplasm enclosed by plasmalemma). When examined by electron microscopy, cytoplasts were found to be approximately 4 microns in diameter and essentially granule free. Cytoplasts exposed to fMet-Leu-Phe (0.1 microM) generated superoxide anion after a lag of 16 sec but released no detectable beta-glucuronidase, lysozyme, or elastase. Aggregation of cytoplasts, as measured by changes in light transmission, was also activated by fMet-Leu-Phe; no lag period was observed. Electron microscopy of the aggregates demonstrated clusters of cytoplasts with a scalloped appearance. Superoxide anion generation and aggregation of cytoplasts were also activated by phorbol 12-myristate 13-acetate, concanavalin A, and leukotriene B4. Exposure of cytoplasts to the dye 3,3'-dihexyloxacarbocyanine iodide (DiOC6(3)] led to dye uptake and enhancement of fluorescence, implying that the vesicles were sealed and maintained a membrane potential across the plasmalemma. Exposure of DiOC6(3)-loaded cytoplasts to fMet-Leu-Phe and PMA caused a rapid loss of dye fluorescence that was not inhibited by CN-, compatible with their lack of mitochondria. Exposure of dye-loaded cytoplasts to concanavalin A or leukotriene B4 caused an increase in fluorescence--i.e., a hyperpolarization. These results demonstrate that degranulation is not a prerequisite for aggregation or superoxide anion generation. The retention of ionic gradients and changes in membrane potential, as measured by DiOC6(3) fluorescence changes, suggest a fundamental role for ionic movements in activating superoxide anion generation and aggregation

Neutroplasts, which are vesicles consisting of cytoplasm enclosed by plasmalemma, have been prepared and found to be incapable of degranulation in response to f-Met-Leu-Phe. However, neutroplasts generate superoxide anion in response to f-Met-Leu-Phe and PMA, and therefore, degranulation is not essential for superoxide anion generation. In addition, neutroplasts aggregate and show shape changes in response to f-Met-Leu-Phe and PMA, and thus degranulation is not essential for aggregation. Neutroplasts take up the carbocyanine dye DiOC6(3), thereby providing evidence for ionic gradients. Dye-loaded neutroplasts show fluorescence changes in response to a variety of stimuli. This response is not CN--inhibitable; therefore, activation of neutroplasts is associated with changes in membrane potential at the plasmalemma, suggesting a role for ion fluxes in the activation sequence for aggregation and superoxide anion generation