Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma

Genetic defects in the IFN-gamma response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-gamma may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-gamma and IFN-gamma production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-gamma was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-gamma to increase production of TNF-alpha by both autologous and normal donor PBMCs, and recovery of exogenous IFN-gamma from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-gamma-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-gamma. The purified anti-IFN-gamma antibody was shown to be functional first in blocking the upregulation of TNF-alpha production in response to endotoxin; second in blocking induction of IFN-gamma-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-gamma pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.     

Immunoglobulin administration to fetuses with anemia due to alloimmunization to D

BACKGROUND: The purpose of this study was to examine fetal tolerance of high-dose intravenous immunoglobulin (IVIG), given directly at the time of intravascular transfusion, and its effects on fetal hemolysis and pregnancy outcome in the setting of alloimmunization to D. STUDY DESIGN AND METHODS: Thirteen consecutive D+ fetuses requiring transfusion for maternal alloimmunization received high-dose IVIG (1.0 g/kg) and red cell transfusions. Twenty-four previous, consecutive fetuses with maternal anti-D served as controls. The schedules for subsequent transfusions were the same in the two groups. RESULTS: High-dose IVIG was well tolerated by all fetuses. In the IVIG group, daily decreases in hematocrit were smaller than those in controls after the second administration of IVIG (mean hematocrit decrease, 0.72 percent/day vs. 1.45 percent/day; p = 0.007). No significant difference was found in the total number of fetal transfusions, the gestational age at delivery, the duration of neonatal intensive care, the number of neonates requiring postnatal transfusion therapy, and perinatal mortality. CONCLUSION: In this small pilot study, direct administration to fetuses of IVIG with red cell transfusions was well tolerated and appeared to have a beneficial effect on fetal hemolysis.     

Immunoglobulin administration to fetuses with anemia due to alloimmunization to D

BACKGROUND: The purpose of this study was to examine fetal tolerance of high-dose intravenous immunoglobulin (IVIG), given directly at the time of intravascular transfusion, and its effects on fetal hemolysis and pregnancy outcome in the setting of alloimmunization to D.
STUDY DESIGN AND METHODS: Thirteen consecutive D+ fetuses requiring transfusion for maternal alloimmunization received high-dose IVIG (1.0 g/kg) and red cell transfusions. Twenty-four previous, consecutive fetuses with maternal anti-D served as controls. The schedules for subsequent transfusions were the same in the two groups.
RESULTS: High-dose IVIG was well tolerated by all fetuses. In the IVIG group, daily decreases in hematocrit were smaller than those in controls after the second administration of IVIG (mean hematocrit decrease, 0.72 percent/day vs. 1.45 percent/day; p = 0.007). No significant difference was found in the total number of fetal transfusions, the gestational age at delivery, the duration of neonatal intensive care, the number of neonates requiring postnatal transfusion therapy, and perinatal mortality.
CONCLUSION: In this small pilot study, direct administration to fetuses of IVIG with red cell transfusions was well tolerated and appeared to have a beneficial effect on fetal hemolysis.     

Blood to brain to the rescue

Neurodegeneration occurs in the majority of the more than 40 known lysosomal storage diseases. Since the nervous system in these disorders can be globally affected, effective treatment would require persistent widespread correction. Biffi et al. show such correction is possible in a mouse model of metachromatic leukodystrophy by the transplantation of hematopoietic cells genetically modified to overexpress the missing lysosomal enzyme. The results reveal a nervous system damage-response pathway that can be harnessed to provide therapy to the nervous system in these serious disorders.