IgM In Cord Blood Research Articles

Interferon-γ and Interleukin-10 Responses during Clinical Malaria Episodes in Infants Aged 0-2 Years Prenatally Exposed to Plasmodium falciparum: Tanzanian Birth Cohort.

Background Infants born to mothers with placental malaria are prenatally exposed to Plasmodium falciparum antigens. However, the effect of that exposure to subsequent immune responses has not been fully elucidated. This study aimed at determining the effect of prenatal exposure to P. falciparum on Interleukin-10 and Interferon-γ responses during clinical malaria episodes in the first 24 months of life. Methods This prospective cohort study involved 215 infants aged 0-2 years born to mothers with or without placental malaria. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of IL-10 and IFN-γ in infants and detect IgM in cord blood. Data were analyzed using SPSS version 20. Findings Geometric mean for IFN-γ in exposed infants was 557.9 pg/ml (95% CI: 511.6-604.1) and in unexposed infants it was 634.4 pg/ml (95% CI: 618.2-668.5) (P=0.02). Mean IL-10 was 22.4 pg/ml (95% CI: 19.4-28.4) and 15.1 pg/ml (95%CI: 12.4-17.6), respectively (P=0.01). Conclusions Prenatal exposure to P. falciparum antigens significantly affects IL-10 and IFN-γ responses during clinical malaria episodes in the first two years of life.

The Antibody Germline/Maturation Hypothesis, Elicitation of Broadly Neutralizing Antibodies Against HIV-1 and Cord Blood IgM Repertoires.

We have previously observed that all known potent broadly neutralizing antibodies (bnAbs) against HIV-1 are highly divergent from their putative germline predecessors in contrast to bnAbs against viruses causing acute infections such as henipaviruses and SARS CoV, which are much less divergent from their germline counterparts. Consequently, we have hypothesized that germline antibodies may not bind to the HIV-1 envelope glycoprotein (Env) because they are so different compared to the highly somatically mutated HIV-1-specific bnAbs. We have further hypothesized that the immunogenicity of highly conserved epitopes on the HIV-1 envelope glycoproteins (Envs) may be reduced or eliminated by their very weak or absent interactions with germline antibodies and immune responses leading to the elicitation of bnAbs may not be initiated and/or sustained. Even if such responses are initiated, the maturation pathways are so extraordinarily complex that prolonged periods of time may be required for elicitation of bnAbs with defined unique sequences. We provided the initial evidence supporting this antibody germline/maturation hypothesis, which prompted a number of studies to design vaccine immunogens that could bind putative germline predecessors of known bnAbs and to explore complex B cell lineages. However, guiding the immune system through the exceptionally complex antibody maturation pathways to elicit known bnAbs remains a major challenge. Here, we discuss studies exploring the antibody germline/maturation hypothesis as related to elicitation of bnAbs against HIV-1 and present our recent data demonstrating the existence of germline-like precursors of VRC01 antibodies in a human cord blood IgM library.

Human anti-60 kD heat shock protein autoantibodies are characterized by basic features of natural autoantibodies

Anti-human Hsp60 autoantibodies--known risk factor of atherosclerosis--were investigated in a mouse model and in samples of healthy subjects: polyreactivity, presence in cord blood samples of healthy newborns and life-long stability were tested. In IgM hybridoma panel from mouse spleens, polyreactivity of anti-Hsp60 autoantibodies was studied. In healthy pregnant women, umbilical vein and maternal blood samples were collected after childbirth, anti-Hsp-60 and -65 IgM and IgG levels were measured. Life-long stability of anti-Hsp-60 levels was studied on healthy patients during 5 years. ELISA was used in all studies. Polyreactivity of IgM clones of newborn mice and lifelong stability of these autoantibodies in healthy adults were established. IgM anti-Hsp60 autoantibodies in cord blood of healthy human infants were present, however, there was no correlation between maternal and cord blood IgM anti-Hsp60 concentrations. It is proposed that presence of anti-Hsp60 autoantibodies--as part of the natural autoantibody repertoire--may be an inherited trait. Level of anti-Hsp60 autoantibodies may be an independent, innate risk factor of atherosclerosis for the adulthood.

Diagnosis of congenital toxoplasmosis: prenatal and neonatal evaluation of methods used in Toulouse University Hospital and incidence of congenital toxoplasmosis

The aim of this study was to determine the incidence of congenital toxoplasmosis (CT) and to assess the performances of prenatal and neonatal diagnoses. From 1994-2005, in Toulouse University Hospital, France, amniocentesis was performed on 352 pregnant women who were infected during pregnancy. All women were treated with spiramycin and pyrimethamine-sulfadoxine when prenatal diagnosis was positive. Among the 275 foetuses with follow-up, 66 (24%) were infected. The transmission rates of Toxoplasma gondii were 7%, 24% and 59% in the first, second and third trimesters, respectively. The sensitivity and specificity of PCR on amniotic fluid (AF) were 91% and 99.5%, respectively. One case was diagnosed by mouse inoculation with AF and six cases were diagnosed by neonatal or postnatal screening. The sensitivity and specificity of PCR on placentas were 52% and 99%, respectively. The sensitivity of tests for the detection of specific IgA and IgM in cord blood was 53% and 64%, respectively, and specificity values were 91% and 92%. In conclusion, PCR performed on AF had the highest levels of sensitivity and specificity for the diagnosis of CT. This permits an early diagnosis of most cases and should be recommended.

Patients with abnormal IgM levels: assessment, clinical interpretation, and treatment

INTRODUCTION This review of the role of IgM in cognate immunity is part of a series on ambulatory diagnoses and management of primary immune deficiency diseases edited by Chitra Dinakar, University of Missouri.1 IgM is phylogenetically the earliest antibody class identified and the first immunoglobulin isotype to appear in the circulation after exposure to a new antigen. IgM plays an important role in the ontogeny of B cells and in early cognate immune responses.2 VDJ rearrangement of the immunoglobulin heavy chain occurs at the pre– B-cell stage, when light chains are still of the surrogate type ( 5/VpreB). Further maturation leads to immature B cells, which express surface IgM and IgD and carry and light chains, creating a functional B-cell receptor that allows antigen recognition and further development into unswitched memory B cells (IgM /D , CD27 ). After interaction with the T-cell receptor of antigen-specific CD4 T cells via major histocompatibility complex II and costimulatory molecules (CD40 ligand [CD40L]/CD40, inducible costimulator [ICOS]/ICOS ligand), mature B cells undergo isotype switching, resulting in B cells expressing CD27 and IgG, IgA, or IgE. Whereas IgM is responsible for rapid and early generation of antibody, long-term humoral immunity is initiated by the production of high-affinity IgG or IgA antibody. The demonstration of IgM antibodies to a specific infectious agent can be used as an indicator of recent infection. The presence of IgM in cord blood ( 20 mg/dL) may indicate prenatal infection because IgM antibody cannot be acquired from the mother by transplacental passage. In infants, IgM serum levels increase rapidly from a mean of 11 mg/dL at term to 55 mg/dL at 1 year of age. By 2 years, IgM concentration is approximately 60% of that in adults. IgM is expressed as a monomer on the surface of naive and mature unswitched B cells, where it forms the antigen receptor complex together with the coreceptors Ig and Ig . If secreted, most IgM forms a pentameric complex, which stays mostly (70% to 80%) intravascular. Its half-life is approximately 6 days, in contrast to IgG, which has a half-life of 21 to 28 days. IgM antibodies are uniquely efficient in agglutination and are highly avid because of their multimeric nature and strong complement fixation.

Birth Outcomes Following West Nile Virus Infection of Pregnant Women in the United States: 2003-2004

Congenital West Nile virus (WNV) infection was first described in a single case in 2002. The proportion of maternal WNV infections resulting in congenital infection and clinical consequences of such infections are unknown. In 2003 and 2004, women in the United States who acquired WNV infection during pregnancy were reported to the Centers for Disease Control and Prevention by state health departments. Data on pregnancy outcomes were collected. One of the maternal WNV infections was identified retrospectively after the infant was born. Maternal sera, placenta, umbilical cord tissue, and cord serum were tested for WNV infection by using serologic assays and reverse-transcription polymerase chain reaction. Infant health was assessed at delivery and through 12 months of age. Seventy-seven women infected with WNV during pregnancy were clinically followed in 16 states. A total of 71 women delivered 72 live infants; 4 women had miscarriages, and 2 had elective abortions. Of the 72 live infants, 67 were born at term, and 4 were preterm; gestational age was unknown for 1. Of 55 live infants from whom cord serum was available, 54 tested negative for anti-WNV IgM. One infant born with umbilical hernia and skin tags had anti-WNV IgM in cord serum but not in peripheral serum at age 1 month. An infant who had no anti-WNV IgM in cord blood, but whose mother had WNV illness 6 days prepartum, developed WNV meningitis at age 10 days. Another infant, whose mother had acute WNV illness at delivery, was born with a rash and coarctation of the aorta and had anti-WNV IgM in serum at 1 month of age; cord serum was not available. A fourth infant, whose mother had onset of WNV illness 3 weeks prepartum that was not diagnosed until after delivery, had WNV encephalitis and underlying lissencephaly detected at age 17 days and subsequently died; cord serum was not available. The following major malformations were noted among live-born infants: aortic coarctation (n = 1); cleft palate (n = 1); Down syndrome (n = 1); lissencephaly (n = 1); microcephaly (n = 2); and polydactyly (n = 1). One infant had glycogen storage disease type 1. Abnormal growth was noted in 8 infants. Of 72 infants followed to date in 2003 and 2004, almost all seemed normal, and none had conclusive laboratory evidence of congenital WNV infection. Three infants had WNV infection that could have been congenitally acquired. Seven infants had major malformations, but only 3 of these had defects that could have been caused by maternal WNV infection based on the timing of the infections and the sensitive developmental period for the specific malformations, and none had any conclusive evidence of WNV etiology. However, the sensitivity and specificity of IgM testing of cord blood to detect congenital WNV infection are currently unknown, and congenital WNV infection among newborns with IgM-negative serology cannot be ruled out. Prospective studies comparing pregnancy outcomes of WNV-infected and -uninfected women are needed to better define the outcomes of WNV infection during pregnancy.

Severe congenital cytomegalovirus infection with fetal hydrops in a cytomegalovirus-seropositive healthy woman

We report the case of a woman whose two consecutive pregnancies resulted in intrauterine fetal death due to severe congenital cytomegalovirus infection. In both pregnancies, congenital cytomegalovirus infection was prenatally diagnosed on the basis of detection of cytomegalovirus DNA and specific IgM in cord blood. This case suggests that severe congenital cytomegalovirus infection can occur even in seropositive healthy women.

Incidence, clinical spectrum, and outcome of intrauterine infections in neonates.

A prospective study was undertaken on the incidence of intrauterine infections by screening 1302 cord blood samples for total IgM by radial immunodiffusion. Specific IgM against cytomegalovirus (CMV), rubella and Toxoplasma were estimated in cord blood samples found to contain total IgM > 20 mg/dl. All these neonates were examined at birth and at discharge. Cord blood samples with total IgM > 20 mg/dl were further screened for specific IgM against rubella, CMV and Toxoplasma. Neonates found to have positive specific IgM were followed-up for hearing, opthalmological and developmental assessment. Raised cord blood (IgM > 20 mg/dl) was found in 270/1302 (20.6 per cent). Mean birth weight was comparable in babies with raised (> 20 mg/dl) or low (< 20 mg/dl) cord blood total IgM. Incidence of prematurity and low birth weight were not statistically different in babies with raised cord blood IgM when compared to those with low cord blood IgM levels. Similarly, incidence of intrauterine growth retardation (IUGR) idiopathic was similar in two groups. Specific IgM for rubella was found to be positive in eight (0.6 per cent). Of these, three had symptomatic rubella infection. Two mothers of these symptomatic babies had exanthematous viral illness during first trimester. Specific IgM for CMV was found to be positive in 23 (1.8 per cent) while two infants had symptomatic CMV disease. None of the babies was found to have specific IgM against Toxoplasma. One baby with symptomatic CMV disease and one with rubella died. Another baby with symptomatic CMV disease developed neonatal hepatitis which improved on follow-up but the infant went on to develop sensorineural deafness. All other asymptomatic babies with specific IgM positive against rubella and CMV were found to have normal vision, hearing and development on follow-up.

Herpes Simplex Virus DNA in Amniotic Fluid without Neonatal Infection

Twenty-one pregnant women were studied to determine the distribution of herpes simplex virus (HSV): 10 had symptomatic genital herpes, including 1 with primary cervical HSV infection, and 11 had asymptomatic genital herpes. Samples from vesicles, the cervix, and amniotic fluid (AF) were analyzed with 2 separate polymerase chain reaction (PCR) tests and with viral culture. For newborns, clinical examinations and pharyngeal HSV cultures were performed, and cord blood IgM antibodies to HSV were measured. HSV DNA was present in the AF of 3 women with symptomatic HSV infection, but all cultures were negative. HSV was detected more often with PCR than with culture, in both vesicle and cervical samples. For the asymptomatic group, all AF samples were negative, whereas 4 cervical samples were positive by PCR (none were positive by culture). All isolates were HSV type 2. All infants were healthy, and none had cord blood IgM antibodies to HSV, including those with PCR-positive AF.

The Self‐Reactive Antibody Repertoire of Normal Human Serum IgM is Acquired in Early Childhood and Remains Conserved Throughout Life

The authors have used a quantitative immunoblotting technique to analyse the antibody repertoire of IgM in cord blood and in the serum of young children, young adult males and aged males directed towards antigens in homologous tissues utilized as sources of self antigens. The reactivities of IgM with self antigens exhibited striking homogeneity and invariance among newborns. Self-reactive IgM repertoires of children, young adults and aged males were markedly conserved among individuals and comprised most of the anti-self reactivities that prevailed in neonates. Reactivities of IgM with bacterial antigens showed a high degree of homogeneity among newborns but were more diverse in children, young adults and elderly individuals. Diversity of IgM reactivities with self and non-self antigens did not vary significantly with aging. Principal component analysis (PCA) and linear discriminant analysis (LDA) of the data discriminated between self-reactive IgM repertoires of newborns and children, but failed to discriminate between repertoires of children, young adults and aged males. The data indicate that the self-reactive antibody repertoire of IgM differentiates during the first years of life and remains relatively constant thereafter.

Neonatal lupus erythematosus. Report of serological and immunogenetic studies in twins discordant for congenital heart block

Autoantibody, HLA studies and C4 phenotypes were performed on twins discordant for isolated congenital heart block. Serum from the mother and cord blood from the infants revealed Ro(SSA) and La(SSB) antibodies in all three sera. No significant difference in Ro(SSA) antibody titre was noted in the cord blood of either twin when compared with maternal titres, as detected by a sensitive ELISA assay. The infants' mother was HLA-DR3 positive. Both infants had identical HLA and C4 phenotypes. Immunoblot analysis revealed that sera from both mother and infants reacted with the 52-kDa Ro(SSA) macromolecule. Quantitative cord blood IgM levels were not elevated in either twin. This study indicates that placental transfer of anti-Ro(SSA) or anti-La(SSB) alone to the fetus is not sufficient for the expression of congenital complete heart block. We conclude from this experiment of Nature that there must be a second event determining which infant develops complete heart block, but this is unknown at present.

Prevalence of genital herpes simplex infection and abnormal vaginal cytology in late pregnancy in asymptomatic patients

A study was undertaken to determine the prevalence of genital herpes simplex virus (HSV) infection in 809 asymptomatic, late pregnant women attending the antenatal clinic (ANC) at Ramathibodi Hospital. There was only one case where the cervico-vaginal swab specimen was positive for HSV by cultivation and the biotin-streptavidin enzyme-linked immunosorbent assay (B-SA ELISA), for detection of viral antigens. This gave a prevalence rate of 0.12%. The anti-HSV IgM in cord blood of the infant born to this mother was negative. The Papanicoulaou (Pap) smear was performed in 554 cases, including the above patient, but none showed evidence of HSV infection. The high prevalence of lower genital tract infection in these subjects was noted in both Pap smear (31.05%) and wet preparation of the cervico-vaginal discharge (46.72%). Thus, examination of the cervico-vaginal discharge during late pregnancy should be of benefit to the patients, in revealing asymptomatic infections of the lower genital tract.

COMPARATIVE STUDY BETWEEN THE METHODS OF DOUBLE DIFFUSION IN GEL AND RADIAL IMMUNODIFFUSION OF IgA AND IgM IN CORD BLOOD

In order to find a simple and low cost method that could be used for routine determination of IgA and IgM in cord blood for screening of congenital infections, we studied comparatively the method of Double Diffusion in Gel Ouchterlony (DD) with the method of Radial Immunodiffusion-Mancini (RID), commonly utilized. Cord blood samples were obtained from 85 newborns and IgA and IgM were determined concomitantly by the two methods. The preliminary results showed 11 cases where the determinations of IgM of IgA were negative by RID but positive by DD with high titles. A repeated dosage by RID with serum diluted by half or using immunodiffusion plates for higher concentrations, showed positiveness for these inrnunoglobulins, proving therefore, the importance of double diffusion in detecting falsely negative results obtained by the radial immunodiffusion method. In 6% of the cases, IgM values obtained by RID were higher than 20 mg/dl were detected from title 1/2 up, corresponding to 31.76% of the studied population. For screening of congenital infections, IgM titles equal or superior to 1/2 by DD should be complemented quantitatively by RID. Statistic analyses showed a parallelism between these two methods. Taking into account its low cost and simplicity, the method of double of diffusion in gel is recomended for the routine determination og IgA and IgM in cord blood.

A pilot study of the frequency and significance of placental villitis.

The prevalence of inflammatory villous lesions was determined in a prospective study of 120 consecutive placentas. Cord blood IgM level was measured as an indicator of fetal intrauterine infection, and the birthweights of the infants were noted. Ten cases of villitis were found. Two infants had elevated cord blood IgM and one of them also had amniotic infection. As only one case of villitis had corroborative evidence of transplacental intrauterine infection, 90% of the lesions require an alternative explanation. The severity of the lesions correlated with the presence of low birthweight. The quality of the inflammatory infiltrate was also considered. Only one case included plasma cells; the remainder showed lymphohistiocytic infiltration. The case with plasmacytic infiltration was the one with elevated cord blood IgM. It is concluded that placental villitis is usually not an infective condition and its aetiology remains unknown.

Transplacental passage of influenza A/Bangkok (H3N2) mimicking amniotic fluid infection syndrome

Influenza virus infection complicating pregnancy remains a matter of concern because of the frequency of these infections and possible associated increased maternal and perinatal risks. Influenza A/Bangkok (H3N2) infection occurred in a gravid woman in association with fever, chills, and uterine tenderness and contractions together with maternal and fetal tachycardia. Initial evaluations led to consideration of amniotic fluid infection syndrome with planned termination of the pregnancy. Examination of amniotic fluid obtained by amniocentesis showed neither microorganisms nor neutrophils, and close monitoring and supportive measures were continued. Amniotic fluid and maternal nasopharyngeal washing both yielded influenza A/Bangkok (H3N2). Mother and fetus were closely monitored until term. Cord blood samples demonstrated hemagglutination inhibition and complement fixation antibody titers of 1:32 and >1:512, respectively. Cord blood IgM and IgA hemagglutination inhibition antibody concentrations were 6,400 and 3,200 μg/ml, respectively, consistent with transplacental infection. This is the first confirmation of transplacental influenza infection. This generally self-limited viral infection maymimic the amniotic fluid infection syndrome and put mother and fetus at risk for potentially harmful untimely delivery.

The effect of fetal age, birth weight, and sex on cord blood immunoglobulin values

In order to determine the role played by fetal “factors” in fetal immunoglobulin levels, cord blood samples from 176 normal infants were analyzed for the relationship between immunoglobulin concentration and the gestational age, birth weight, and the sex of the fetus. Cord blood IgM and IgG both increased with gestational age until term, while IgA, its subclasses IgA1 and IgA2, and IgD were unaffected by gestational age. IgM and IgG were higher in fetuses weighing 2,000 grams or more, while IgA, IgA1, and IgA2 were not influenced by birth weight. Cord blood immunoglobulin values were the same in male and female infants. The interrelationship between cord blood immunoglobulin clss and subclass concentrations was examined in two ways: (1) The correlation coefficient r for paired samples was calculated between immunoglobulin concentrations in individual cord sera. (2) Student's t test for the mean was used to compare subgroups of the entire sample populations, divided into high, intermediate, and low immunoglobulin values. IgM and IgG and IgM and IgD were correlated. The data obtained indicate the need to consider the gestational age and birth weight of a neonate in the use of cord blood immunoglobulin values to evaluate the possibility of fetal infection.

Latent herpes cervicitis and mixed cervical carcinoma

diovascular defects or cataracts or simply the presence of a lymphocyte transforming agent in the cord blood of an otherwise asymptomatic neonate. • 4 This report documents severe, multiple congenital anomalies in an infant exposed to the EBV from conception to delivery. It differs from previously reported cases in its widespread tissue involvement, possibly representing the congenital infection in its severest form. The EBV may cause a spectrum of involvement in the congenitally infected offspring ranging from the subclinical type to severe deformity and death. Its incidence is difficult to define, but it is probably an uncommon cause of congenital malformation. The absence of cord blood IgM levels in our patient is consistent with the report of Chang and Blankenshipa in that infection occurred prior to the development of immunocompetency in the fetus. Also, congenitally infected infants with low cord blood lgM levels were stillborn or died in utero with significantly greater frequency. The place of the EB V in perinatal infections is strongly implied both by its close physical relationship to other known viral teratogens and by the spectrum of perinatal involvement just described. The question of its importance and prevalence as a teratogen cannot be answered at this time.

FETAL EFFECTS OF CONGENITAL CYTOHEGALOVIRUS INFECTION (C-CMV)

Ninety-seven newborns with C-CMV observed in our unit over the past 10 years were examined for evidence of fetal maldevelopment. Birth dates were evenly distributed with respect to season. Seventy-nine were asymptomatic at birth of whom 54 were diagnosed because of elevated levels of IgM in cord blood and the remainder identified in a prospective study. Eighteen manifested disease at birth and 6 of this group expired in the neonatal period. Males predominated in the symptomatic group (13/18) whereas an equal sex ratio (43/39) was noted in those with subclinical infection (SI). Mean birth weight (3076 grams) as well as rates of gestational prematurity (GP) (4.1%) and intrauterine growth retardation (12.1%) for those with SI were almost identical to the control population. Similarly, the mean weight/length3 and length/head circumference ratios were not different from expected values. In contrast, among the ill neonates the mean birth weight was 2081 grams and only 2 of 18 were full term and normally grown. Of the remainder, 12 were term infants with intrauterine growth retardation and 4 manifested GP of whom 3 were normally grown and 1 was growth retarded. The patterns of growth failure varied with a tendency toward equal decrements in weight, length and head circumference for symptomatic patients. Structural anomalies occurred in the brain, genitalia, integument and limbs of 5, 7, 1 and 3 patients, respectively, for a total of 15 infants so afflicted.

Cord blood IgM and suspected congenital rubella

Cord blood IgM and suspected congenital rubella

Intestinal absorption of immunoglobulins by newborn infants.

Intestinal absorption in newborn infants of immunoglobulins present in colostrum was studied by measuring the concentrations of immunoglobulins IgA, IgG, and IgM in cord blood and following the changes in the serum of the infant on the 5th day after birth. In infants who did not receive colostrum, a marked fall in IgG levels was observed on the 5th day after birth as compared to levels at birth. The concentrations of IgA and IgM showed marginal changes. In contrast, colostrumfed infants showed significant increases in the concentration of IgG. Levels of all 3 immunoglobulins on the 5th day were significantly higher in the serum of colostrumfed infants as compared to those who did not receive colostrum. It is suggested that immunoglobulins present in colostrum are to some extent absorbed from the intestinal tract of newborn infants, and this may have some physiological significance in the resistance to infection during the early neonatal period.