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Taking aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy may predispose infants to developing persistent pulmonary hypertension of the newborn (PPHN). PPHN causes respiratory failure in otherwise normal full-term infants. NSAIDs and aspirin inhibit prostaglandin production, which animal studies have revealed can cause lung circulation complications after birth. Researchers interviewed mothers of 103 infants with PPHN who were of normal weight at birth and free of congenital anomalies and compared their responses with mothers of 298 matched healthy infants. Mothers of infants with PPHN were five times more likely to have taken aspirin and six times more likely to have taken NSAIDs. Mothers who smoked were twice as likely to have infants with PPHN; however, the effects of smoking could not be distinguished statistically from the effects of low maternal education and illicit drug use. Smoking could predispose infants to PPHN because it causes chronic oxygen lack, another factor animal studies have shown to cause lung circulation complications., Objective. Prenatal causation of persistent pulmonary hypertension of the newborn (PPHN) is suggested by a specific pattern of pulmonary vascular remodeling observed immediately after birth in some infants with fatal PPHN. The goal of this study was to determine whether PPHN is associated with fetal exposure to: (1) tobacco and marijuana smoking (ie, contributors to fetal hypoxemia), (2) consumption of aspirin and other nonsteroidal antiinflammatory drugs (ie, inhibitors of prostaglandin synthesis), and (3) cocaine use (ie, a contributor to vasospasm). Design. Case-control interview study. Setting. Two Harvard-affiliated newborn intensive care units. Participants. Mothers of case infants who had PPHN or who met criteria for the referent group. Interventions. During July 1985 through April 1989, we interviewed mothers of 103 infants with PPHN and 298 control infants. Because of potential selection bias that might result from recruiting only inborn control infants even though two-thirds of cases were outborn, separate analyses compared the 103 total and 35 inborn infants with PPHN with the 298 inborn control infants. Multivariate analyses were used to adjust for potential confounding factors, including maternal education and Medicaid health insurance (ie, two markers of socioeconomic status), other antenatal factors found to be associated with PPHN (ie, maternal urinary tract infection and diabetes mellitus), and the infant's sex. Main Outcome Measures. Self-reported use or consumption of tobacco, marijuana, cocaine, aspirin, and other nonsteroidal antiinflammatory drugs during pregnancy. Results. The adjusted odds ratios (and 95% confidence intervals) for maternal pregnancy exposures to the factors of principal interest among the total study population were: aspirin, 4.9 (1.6-15.3); and nonsteroidal antiinflammatory drugs, 6.2 (1.8-21.8); for the inborn group they were: aspirin, 9.6 (2.4-39.0); and nonsteroidal antiinflammatory drugs, 17.5 (4.3-71.6). Although the association between tobacco smoking during pregnancy and PPHN was elevated in univariate analyses, with odds ratios (and 95% confidence intervals) of 2.0 (1.2-3.4) and 1.3 (0.6-3.3) for total and inborn populations, respective the relationship was not significant after adjustment for all other factors in the final logistic regression model. Acknowledged illicit drug use was too infrequent (3.2%) to evaluate. Conclusion. Maternal consumption of nonsteroidal antiinflammatory drugs and aspirin during pregnancy or the reasons these drugs were ingested seem to contribute to an increased risk of PPHN. Pediatrics 1996;97:658 - 663; newborn infant, diseases; hypertension, pulmonary, persistent fetal circulation, aspirin; nonsteroidal antiinflammatory drugs; smoking; drug abuse; socioeconomic status; diabetes mellitus. ABBREVIATIONS. PPHN, persistent pulmonary hypertension of the newborn; NSAID, nonsteroidal antiinflammatory drug; ECMO, extracorporeal membrane oxygenation; OR, odds ratio; UTI, urinary tract infection; SES, socioeconomic status., Persistent pulmonary hypertension of the newborn (PPHN) is an important cause of profound respiratory failure in newborns, occurring at a rate of 1 in 600 to 1 in 1500 live [...]

Low birth weight (LBW), less than 3.6 pounds (1,750 grams), is associated with a poor infant outcome. LBW infants are at risk for periventricular-intraventricular hemorrhage, bleeding in or around the small cavities of the brain. The more severe the hemorrhage, the greater the brain damage. Phenobarbital, an anticonvulsant, is often given to control seizures in infants experiencing severe periventricular-intraventricular hemorrhage. The relationship between the location of the hemorrhage and the neurological deficit sustained has not been well-studied. The neurological outcome of 228 low birth weight infants who initially required mechanical ventilation and phenobarbital therapy to prevent seizures was evaluated. The results of ultrasonographic imaging, the use of high frequency sound to visualize internal structures, were related to motor abnormalities experienced by the surviving infants 18 months later. There were 51 infants with confirmed hemorrhage. Periventricular-intraventricular hemorrhage was related to neurological abnormalities such as decreased grasp maturity, persistent closure of the fingers, decreased parachute reaction (both arms extended when the infant is turned face-down), delayed walking, spastic palsy and abnormal movements. There was an increased risk for a neurological abnormality regardless of the type and location of the hemorrhage. The deficits were similar with and without phenobarbital prophylaxis. The most common abnormalities were abnormal jerky movements, exaggerated flexing of ankle or knee, and poor muscle tone. Infants experiencing substantial enlargement of the brain's ventricles were five times more likely to develop spastic cerebral palsy and delayed walking. They were three times more likely to have poor resistance to stretch and hyperactive, exaggerated knee-ankle reflexes. There is an increased risk for motor and reflex abnormalities among infants who experienced periventricular-intraventricular hemorrhage, particularly those infants having damage to the white matter of the brain. (Consumer Summary produced by Reliance Medical Information, Inc.)

Benoit L, Wang X, Pabst HF, Dutz J, Tan R. J Immunol. 2000;165:3549-3553 Purpose of the Study. X-linked lymphoproliferative disease is a devastating immunodeficiency in which affected males are largely [...]

Purpose of the Study. Several previous studies have documented a subtle abnormality of neutrophil and macrophage function in patients with Wiskott-Aldrich syndrome. This study was designed to investigate the cause of phagocyte dysfunction in Wiskott-Aldrich syndrome. Monocyte/macrophage dysfunction could contribute to the recurrent infections seen in this syndrome. Study Population. Four patients with Wiskott-Aldrich syndrome were studied. Methods. Morphologic changes after stimulation were defined by light microscopy and immunofluorescence for actin. Chemotaxis was measured in a microchamber and superoxide production was defined using a cytochrome c reduction technique. Results. Monocyte chemotaxis responses to macrophage inflammatory protein 1[Alpha] (MIP1[Alpha]), monocyte chemoattractant protein-1 (MCP-1), and formyl-methionylleucyl-phenylalanine (FMLP) were abnormal. Similarly, actin polarization and morphologic polarization were defective in the stimulated monocytes from patients with Wiskott-Aldrich syndrome. Conversely, respiratory burst and upregulation of adhesion molecules was intact after stimulation. Conclusions. Monocyte activities requiring chemotaxis or polarization are defective in patients with Wiskott-Aldrich syndrome. Aberrant leukocyte recruitment to areas of inflammation could contribute to the recurrent infections in this syndrome. Reviewer's Comments. A previous report demonstrated that actin polarization after stimulation of T cells is aberrant in this disorder; therefore, this report is consistent with a global abnormality affecting transduction of cell surface signals to the cytoskeleton. This was also expected based on the molecular characterization of the WASp protein, which is defective in Wiskott-Aldrich syndrome. The WASp protein acts as a docking site for signaling molecules and GTPases implicated in actin polymerization. The implications of these findings is that treatment of patients with biological agents such as cytokines may be beneficial as modulators in particular clinical settings but is unlikely to overcome the defect in this syndrome because it is cell-intrinsic., Badolato R, Sozzani S, Malacarne F, et al. J Immunol. 1998;161:1026-1033 KATHLEEN SULLIVAN, MD, PuD Philadelphia, [...]

Purpose of the Study. X-linked agammaglobulinemia (XLA) is classically described as a pure humoral immunodeficiency in which boys fail to produce mature B cells and as a consequence, make no immunoglobulin. With the advent of genetic testing for this disorder, it has become clear that there are boys with XLA who have small numbers of peripheral blood B cells and small amounts of antibody. This study evaluated the function of the peripheral blood B cells in boys with XLA. Study Population. Five of 9 patients with XLA had detectable peripheral blood B cells. Four of the 5 patients had missense mutations of Btk identified. In the fifth patient, absence of Btk protein was demonstrated by Western blot. Methods. B cell function was evaluated using CD40 crosslinking and interleukin (IL)-4 stimulation. Proliferation, immunoglobulin E (IgE) production, and upregulation of CD23 were measured. In addition, patients were immunized to 0X174. Results. Proliferation, CD23 expression, and IgE production were all normal in the B cell cultures from XLA patients. Although antibody titers after immunization were not normal, XLA patients were capable of responding to the immunization and demonstrated an enhanced response after a secondary immunization suggesting immunologic memory is intact. Significantly, the patients did not undergo isotype switching to IgG on secondary immunization. Conclusions. CD40-mediated B cell function in XLA patients appears to be relatively normal. The authors suggest that this bypass strategy could be used as a potential therapy for XLA. Reviewer's Comments. The function of Btk is incompletely understood. Analysis has been complicated by the fact that murine models of XLA exhibit significant differences from the human disease. This study demonstrates that B cells from patients with Btk mutations are not intrinsically dysfunctional. This implies that Btk may be important in B cell maturation but is dispensible for some functions after maturation. This study also implies that there is a Btk bypass pathway that allows some B cells to mature. Using a Btk bypass therapeutic strategy would have significant theoretical risks but is certainly an approach worth consideration., Nonoyama S, Tsukada S, Yamadori T, et al. J Immunol. 1998;161:3925-3929 KATHLEEN SULLIVAN, MD, PhD Philadelphia, [...]

Purpose of the Study. Common variable immunodeficiency is a polygenic disorder of uncertain cause, which is often associated with autoimmune disease. There appear to be several distinct subtypes of common variable immunodeficiency and one subtype includes patients with granulomatous splenomegaly, decreased numbers of circulating CD4 T cells, and lymphadenopathy. This study investigated whether inherited polymorphisms in the MHC class III region (which includes tumor necrosis factor [TNF]-[Alpha] and lymphotoxin-[Alpha]) contributed to the development of this subtype of common variable immunodeficiency. Study Population. Ninety patients with common variable immunodeficiency were studied. Twenty of those 90 patients had granulomas and were felt to belong to a distinct subgroup. Methods. Eight HLA class I and class II loci were typed using standard polymerase chain reaction (PCR) methods. Three biallelic TNF-[Alpha] polymorphisms were genotyped and three lymphotoxin-[Alpha] polymorphisms were genotyped using allele-specific PCR. Peripheral blood phenotyping was performed using standard flow cytometry techniques. Results. The presence of granulomas correlated strongly with decreased numbers of total T cells, decreased numbers of total B cells, and depletion of naive T cells. This subpopulation of patients with granulomas also had an overrepresentation of the haplotype: A*01-Cw*0701-B*0801-DRBI*0301-DQBI*0201 which contains the TNF-308A polymorphism. In addition, as association between granulomas and the TNF+488A allele was demonstrated. Conclusions. This important study confirms that there is a clinically distinct subset of patients with common variable immunodeficiency and granulomatous disease. This subset appears to have a distinct genetic cause and characteristic derangements of peripheral blood lymphocyte subsets. Reviewer's Comments. TNF is essential for the formation of granulomas and this study hypothesized that inherited differences in TNF production might predispose patients to the granulomatous complications of common variable immunodeficiency. In whites, the TNF-308A polymorphism is in linkage disequilibrium with the haplotype cited above, which makes it difficult to prove whether the TNF polymorphism itself is responsible for the granulomatous complications. Despite this limitation, this study makes a compelling case that overproduction of TNF is implicated in the granulomatous complications of common variable immunodeficiency., Mullighan CG, Fanning GC, Chapel HM, Welsh KI. J Immunol. 1997;159:6236-6241 KATHLEEN SULLIVAN, MD, PhD Philadelphia, [...]

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syndrome and is associated with thymic hypoplasia and diminished T-cell numbers and has a wide spectrum of phenotypic features that include cardiac anomalies, dysmorphic facial features, and hypocalcemia. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. The aims of this study were to investigate the incidence of side effects after live viral vaccine administration in a population with chromosome 22q11.2 deletion syndrome. The high frequency of this syndrome in the population (1:3000 children) mandates a greater understanding of the risks and benefits related to live viral vaccine administration. A retrospective analysis of vaccine adverse events was performed. The data acquisition form evaluated the frequency of live vaccine administration and the consequences of both vaccination and withholding the vaccine. Flow cytometric enumeration of T cells was performed as part of an immunologic evaluation. Thirty-two of 59 responders were vaccinated with the varicella vaccine. Only 9% of patients reported adverse events. However, 63% of unvaccinated children developed chickenpox. Comparison of patients who tolerated the vaccine with those who reported adverse events showed no statistically significant differences in current age (7 vs 5.7 years), age at vaccination (3 vs 2.5 years), or T-cell subset counts: CD3 (1951 vs 2083 cells/ [micro]L), CD4 (1283 vs 1463 cells/[micro]L), and CD8 (530 vs 502 cells/[micro]L). Fifty-two of 59 responders were vaccinated with measles-mumps-rubella (MMR). Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional symptoms. No severe adverse reactions were reported. No patient reported natural disease with measles, mumps, or rubella. There were no statistically significant differences between the T-cell counts in the vaccinated group reporting side effects versus the vaccinated group without side effects (mean CD3 counts: 1928 vs 1736 cells/[micro]L; CD4 counts: 1250 vs 1127 cells/[micro]L; and CD8 counts: 528 vs 483 cells/[micro]L). In our study, patients with chromosome 22q11.2 deletion syndrome had a similar incidence of adverse effects with varicella and MMR vaccines compared with that reported in the general population. All side effects were mild. However, in patients who did not receive the varicella vaccine, an overwhelming 63% contracted the disease. Patients who were not vaccinated against MMR did not develop natural disease. The data suggest that this is a cohort of patients with 22q11.2 deletion syndrome who have tolerated live viral vaccinations without evidence of significant side effects. A prospective study could address whether there are T-cell thresholds below which vaccination is unsafe; however, the information that we present suggests that vaccinating children with chromosome 22q11.2 deletion with live viral vaccines does not carry a significantly higher risk of adverse reactions compared with the general population, provided that they have no evidence of severe immunocompromise.

Purpose of the Study. This large Italian study was designed to investigate the natural history of X-linked agammaglobulinemia (XLA). Although it is among the more common of the primary immunodeficiencies, there is surprisingly little information on optimal management and outcome. This study was designed to characterize the long-term issues facing this patient population. Study Population. Seventy-three males with a definite diagnosis of XLA constitute the study population. Thirty-nine Italian centers participated. This group is relatively old with a mean age of 14 years, and this allows the authors to perform certain longitudinal studies. Methods. All male patients at the 39 centers with hypogammaglobulinemia and B cell numbers Results. There are several surprises in this article. The immunoglobulin G (IgG) levels at enrollment ranged from a low of 7 mg/dL to a high of 891 mg/dL. Most patients, but not all, had very low immunoglobulin A (IgA) levels, and the 10 patients who had an IgA >20 mg/dL typically had normal or near normal immunoglobulin M (IgM) levels, but there was no correlation between IgA/IgM levels and IgG levels. All patients had Conclusions. The spectrum of XLA is clearly broader than was once imagined. Although patients have improved survival in this study compared with earlier studies of XLA patients, there are significant health issues for these patients. Chronic lung disease and sinusitis remain persistent problems. Reviewer's Comments. This is a wonderful study that will lead many people to revise their diagnostic work-up of patients with hypogammaglobulinemia. Questions yet to be addressed are how to improve management and eliminate chronic infections., Plebiani A, Soresina A, Rondelli R, et al. Clin Immunol. 2002;104:221-230 KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Purpose of the Study. Defects in genes involved in the apoptosis (programmed cell death) of lymphocytes have been shown to cause disorders characterized by significant adenopathy and autoimmunity. This study defines a new defect in that category and characterizes the clinical presentation. Mutations in the caspase-8 gene not only affect apoptosis but also affect host defense. This article describes a heretofore unrecognized function of caspase-8 in lymphocyte activation. Study Population. The study relies on a single kindred with 2 affected children and the heterozygous parents and sibling. The carriers of the mutation were asymptomatic. Methods. The authors carefully characterize the apoptosis of cells from the affected children as well as the activation of their lymphocytes. Traditional killing studies were performed to define the defect in apoptosis as well as flow cytometric determinations of T cell activation. Cytokine production and proliferation were also measured to delineate the defect in T cell function. Results. The 2 patients with defects in caspase-8 had significant adenopathy and splenomegaly. These 2 features have been observed in all patients with defects in genes involved in lymphocyte apoptosis. In addition, these patients had several features that appear to be specific for caspase-8 defects. The patients had diminished CD4 counts, elevated CD8 T cell counts, poor responses to immunization, failure to thrive, recurrent herpes infections, and other recurrent infections. Mechanistic studies revealed defective apoptosis attributable to Fas-mediated signals but preserved apoptosis in response to mitochondrial-mediated signals. Western blots suggested that the Fas signal was intact up to recruitment of Fas-associated death domain, but that subsequent recruitment of caspase-8 was defective. Sequencing revealed a homozygous caspase-8 mutation. In addition to the defect in apoptosis, the authors describe a very significant defect in lymphocyte activation that probably accounts for the immunodeficiency phenotype. B cells, T cells, and NK cells are all defective in this disorder. Conclusions. Caspase-8 mutations lead to a disorder characterized by expansion of lymphocytes in secondary lymphoid organs and abnormal lymphocyte activation. Reviewer's Comments. This article is significant for introducing us to a new immunodeficiency and for the demonstration that caspase-8 is involved in lymphocyte activation. The 3 known defects of lymphocyte apoptosis, Fas deficiency, FasL deficiency, and caspase 10 deficiency all have a similar phenotype: the early presentation of significant adenopathy, splenomegaly, and autoimmune disease. Caspase-8 is now known to have an undefined but integral function in lymphocyte activation and the phenotype of patients with caspase-8 deficiency reflects this, with both lymphoid expansion and immunodeficiency., Chun HJ, Zheng L, Ahmad M, et al. Nature. 2002;419: 395-399 KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Purpose of the Study. The disorder IPEX (immunodys-regulation, polyendocrinopathy, enteropathy, X-linked syndrome) is characterized by enlargement of secondary lymphoid structures, diabetes mellitus beginning in early infancy, and chronic enteropathy. The gene defect was identified in 2001 as FOXP3 on the X chromosome. The FOXP3 gene is a member of the forkhead family of transcription factors, however, the basis for IPEX has remained poorly characterized. Previous groups have shown that the immune system is in a state of chronic activation in these patients with overproduction of cytokines and immunoglobulins, but the relationship of these problems to the FOXP3 mutations has been unclear. This article describes work defining the role of the FOXP3 protein product, scurfin, to the manifestation of T cell expansion. Methods. The authors use mouse models including the scurfy mouse, which has an inactive FOXP3 gene and mice transgenic for overexpression of FOXP3. Flow cytometry and histology are used to characterize changes in peripheral T cells and the T cell compartments in secondary lymphoid structures. Results. The scurfin protein is expressed in the thymus but had no demonstrable affect on the phenotype of the scurfy mouse. Overexpression of scurfin in the thymus in a normal mouse had modest affects on various thymic subsets but did not induce any changes in the periphery. Overexpression of scurfin globally in normal mice caused decreased T cell proliferation and interleukin (IL)-2 production. Similarly, overexpression of scurfin inhibited cytolytic T cell activity. Conclusions. The function of scurfin appears to regulate the function and size of the peripheral T cell compartment. Reviewer's Comments. IPEX is an uncommon but nearly always fatal immunodeficiency. Affected boys are often total parenteral nutrition-dependent because of their enteropathy and require very stringent immunosuppression for even short-term survival. Stem cell transplantation may be effective. The importance of this article is in its description of a global overactivity of the T cell compartment. This contributes to our understanding of the pathogenesis of this disorder and reinforces the growing belief that the best management option may be early stem cell transplantation., Khattri R, Kasprowicz D, Cox T, et al. J Immunol. 2002; 167:6312-6320 KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Purpose of the Study. Some patients with severe congenital neutropenia harbor mutations in the carboxyl terminus of the granulocyte colony-stimulating factor (G-CSF) receptor. It is this subgroup of patients with severe congenital neutropenia that is markedly predisposed to acute myeloid leukemia. This predisposition poses a significant hurdle to management. Patients with severe congenital neutropenia are typically treated with G-CSF. In this subgroup, G-CSF could drive leukemogenesis and is contraindicated. This study examines the mechanism underlying the predisposition to malignancy. Methods. Cell lines transfected with both wild-type and mutant G-CSF receptor cDNAs and SHP-1 negative cell lines were used to examine the effect of the mutation on signaling function. Electrophoretic mobility shift assays, Western blots, and transient transfections using reporter constructs were performed. Results. The mutant receptors are paradoxically associated with an increased proliferative response to G-CSF despite the differentiative block in neutrophil development. The G-CSF-receptor contains no intrinsic signaling activity, but activates Src family kinases, STAT 3/5, MAP kinases, and PI3 kinase. SHP-1 acts as a negative regulator. The mutant receptors are unable to interact effectively with SHP-1. The consequences of this impaired negative regulation are prolonged responses in the STAT pathways but not other signaling pathways. The exaggerated responses in the STAT pathways would explain the survival advantage of these cells and their hyperproliferation. Conclusion. Failure of the mutant G-CSF receptors to interact effectively with the negative regulator SHP-1 appears to underlie the predisposition to acute myeloid leukemia. Reviewer's Comments. This study represents an important advance in our understanding of the secondary malignancies occurring in patients with severe congenital neutropenia. It should allow improved risk stratification for patients and could ultimately lead to improved management. Dong F, Qiu Y, Yi T, Touw IP, Larner AC. J Immunol. 2001;167:6447- 6452, KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Purpose of the Study. Major histocompatibility complex (MHC) class II deficiency or the bare lymphocyte syndrome is an autosomal recessive congenital immunodeficiency which typically is associated with a severe combined immunodeficiency (SCID)-like picture. There are 4 gene defects that can cause this disorder: class II trans-activator (CIITA), RFX, RFX5, and RFX-associated protein defects. These are all transcription factors required for the coordinate transcriptional regulation of MHC class II genes. Approximately 70 patients with MHC class II deficiency have been described and the usual course is one of unrelenting infections and death by age 4 unless a bone marrow transplant is performed. This manuscript describes 3 adult siblings who had a mild infection history and were found to have CIITA deficiency. Methods. Monocytes, B cells, and skin dendritic/macrophage cells were stained for MHC class II expression. B cell fusions were performed to identify the complementation group (putative gene defect) and ultimately the CIITA gene was sequenced. Transfection experiments were performed to confirm the functional defect was associated with the identified mutation. Results. A single homozygous mutation was identified in all 3 siblings. This L469P substitution in CIITA results in markedly diminished activity of the transcription factor. Importantly, the activity was not abolished. Conclusions. This is the first CIITA mutation to result in partial activity. All other mutations have been associated with an inability to translocate to the nucleus and none have been able to stimulate transcription. The mild phenotype in these patients could be attributable to the residual activity of the mutant protein. Reviewer's Comments. MHC class II deficiency is characterized by severe recurrent infections, protracted diarrhea, CD4 T cell lymphopenia, immunoglobulin G (IgG)2 subclass and immunoglobulin A (IgA) deficiency, relative preservation of mitogen proliferative responses but absent responses to recall antigens. These 3 siblings had mild infections, aberrant functional antibodies, impaired responses to recall antigens, and CD4 T cell counts at the lower limit of normal. Two of the 3 were IgA-deficient. In all respects, their clinical presentation and laboratory findings represented a mild form of what is typically seen in MHC class II deficiency. The scientific lesson from this article is that the L469 is critical for full function of CIITA. The clinical lesson is that there are probably many patients with mutations in immunologically relevant genes with mild phenotypes that are not easily detected with currently available laboratory analyses. Only a high degree of suspicion and diligence will allow the caregiver to identify the underlying immunodeficiency. Wiszniewski W, Fondaneche M-C, Le Deist F, et al. J Immunol. 2001;167:1787-1794, KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Purpose of the Study. Defects in genes required for the development of T cells often underlie the primary immunodeficiency known as severe combined immunodeficiency (SCID). Many gene defects have been identified in SCID patients although the most common is the X-linked form of SCID that is attributable to defects in the common cytokine receptor chain. This study examined the cause of a novel type of SCID that was associated with minimal surface expression of CD45. CD45 is an abundant cell surface protein with multiple isoforms. It is a protein tyrosine phosphatase that is critical for transmembrane signal transduction. Methods. Peripheral blood mononuclear cells from the patient were examined for expression of CD45 using standard flow cytometry techniques. The CD45 gene was sequenced using polymerase chain reaction. To confirm the role of the mutation in the defective expression of CD45, the mutant cDNA was transfected into Chinese hamster ovary cells. Results. The patient was found to have a homozygous mutation in CD45. The 6bp deletion was located in the extracellular domain. The mutation did not affect transcript stability or translation, but protein was undetectable at the cell surface. This was true for 3 of the 8 isoforms examined and could be presumed to similarly affect all isoforms. Conclusions. The homozygous mutation in CD45 was not found in any normal controls and was found to reproduce the defect in transfection experiments. The authors conclude that this 6bp deletion in the extracellular domain was responsible for the reduced surface expression of CD45 and the patient's SCID. Reviewer's Comments. This particular patient was the first identified as being CD45-deficient in 1997, although the mutation was not identified until this manuscript. It is apparently a rare type of SCID with only 2 patients known to be CD45-deficient. This study demonstrates the importance of the 2 deleted amino acids in the surface expression of CD45 and serves as a reminder of the many types of defects that can potentially be associated with SCID. Tchilan EZ, Wallace DL, Wells RS, Flower DR, Morgan G, Beverley PCL. J Immunol. 2001;166:1308-1313, KATHLEEN E. SULLIVAN, MD, PHD Philadelphia, [...]

Presents an abstract of the research paper `Defective Monocyte Costimulation for IFN-gamma Production in Familial Disseminated Mycobacterium avium Complex Infection: Abnormal IL-12 Regulation,' by D.M. Frucht et al published in a 1996 issue of the `Journal of Immunology.'

Presents an abstract of the study titled `Molecular Genetic Analysis of X-Linked Hypogammaglobulinemia and Isolated Growth Hormone Deficiency,' by D.M. Stewart, D.L. Nelson, published in the 155th volume 1995 issue of `J. Immunol.'