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The immune system of preterm infants is immature, placing them at increased risk for serious immune-related complications. Human milk provides a variety of immune protective and immune maturation factors that are beneficial to the preterm infant's poorly developed immune system. The most studied immune components in human milk include antimicrobial proteins, maternal leukocytes, immunoglobulins, cytokines and chemokines, oligosaccharides, gangliosides, nucleotides, and long-chain polyunsaturated fatty acids. There is growing evidence that these components contribute to the lower incidence of immune-related conditions in the preterm infant. Therefore, provision of these components in human milk, donor milk, or formula may provide immunologic benefits.

OBJECTIVES: Serum C-reactive protein (CRP) has been used as a systemic inflammatory response (SIR) marker in the critical ill, including children after cardiopulmonary bypass surgery. Ventricular assist devices (VAD) have been increasingly used as a bridge support to heart transplantation in children. We aimed to examine the profiles of CRP in children receiving VAD support. METHODS: Charts of 13 children receiving Berlin Heart EXCOR ® from 2005 to 2009 were reviewed. The data obtained prior to and during VAD support included: CRP, white blood cells, inotropes and steroid use, VAD mode and duration of VAD support. Ten patients received left VAD (LVAD) and 3 biventricular VAD (BiVAD). RESULTS: The median duration of VAD support was 59 days (ranged 3–678 days). Pre-VAD CRP was 35 ± 51 mg/l and increased to 109 ± 59 mg/l on days 1–3 after the VAD implantation (P = 0.01), then gradually decreased to 28 ± 28 mg/l by 4 months and normalized by 5 months (P < 0.0001). CRP was higher in BiVAD than in LVAD patients throughout the study period (P = 0.003). CRP positively correlated with the doses of the epinephrine and norepinephrine and the monocyte counts, and negatively correlated with the lymphocyte count. The lymphocyte count was 2.5 ± 0.4 × 10 9 /l prior to implantation, and decreased to 2.1 ± 1.3 × 10 9 /l on days 1– 3( P= 0.5) and then to 0.6 ± 0.1 × 10 9 /l by 6 months (P= 0.08). It tended to be lower in BiVAD patients (P= 0.06). CONCLUSIONS: SIR exists in children prior to VAD support. VAD implantation is associated with a significant and prolonged increase in CRP and a decrease in lymphocyte count, indicating a suppressed immune function, being more pronounced in BiVAD patients.

Inflammatory and metabolic response is an important factor to determine clinical outcomes. However, it remains unknown in children undergoing heart transplantation (HTx). We examined the perioperative changes in the inflammatory and metabolic response markers C-reactive protein (CRP) and prealbumin (PA) in 38 heart-transplanted children. Data obtained prior to and within one month after HTx included CRP, PA, total and differential white blood cell counts, doses of inotropes and immunosuppressants, cultures of blood and body fluids, duration of cardiopulmonary bypass (CPB), aortic cross clamp and donor heart ischemia, and days in the intensive care unit (ICU) and hospital. CRP was 32±49 mg/L before HTx, increased to 130±55 mg/L on postoperative day 1-2, and decreased to 21±31 mg/L by one month after HTx. PA was 0.15±0.06 g/L before HTx, decreased to 0.12±0.03 g/L on postoperative day 1-2, and then gradually increased to 0.21±0.10 g/L by one month after HTx. Postoperative CRP positively correlated with epinephrine dosage and CPB duration. PA positively correlated with age. In conclusion, inflammatory and metabolic response is present before HTx and acutely intensified after HTx. It may be mainly influenced by CPB duration and cardiovascular function status.

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a.familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28, Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18, HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 30 HLA homozygous individuals, of these 15 were HLA-A2, B12/A2, B12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.

In order to further elucidate the genetics of Graves' disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent-child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA-A11, Bw51, Cw5, Cw-, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA-A1, B8, Cw-, DRw3, BfS and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent-child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the non-shared haplotypes.

One hundred and thirty members of a family with 33 cases of Dystrophia myotonica (Dm) were tested for various genetic markers including Km, Jk, Lu and Se. All individuals tested were Lua negative, but many were heterozygous for the other markers. Except for two cases all patients with Dm were positive for Km3 and Jka and they were secretors. Assuming the genes are linked and that the order of the loci is Km, Jk, Lu, Se, Dm, then there were 22 meioses informative for Dm and in 10 of these a recombination must have occurred between two of the five loci. Looking at individual pairs of loci, there were no recombinations between Km and Jk in seven informative meioses, three recombinations out of 10 meioses informative for Jk/Se, no recombinations between Se and Dm in five informative meioses and three recombinations out of 12 meioses informative for Jk/Dm.

Human leukocyte antigen (HLA)-DR-positive synovial fibroblasts are frequently observed in rheumatoid arthritis (RA) and may be implicated in the autoimmune reaction because RA is associated with certain HLA-DRB1* alleles. The question of whether components of the class II antigen presentation pathway and specific DRB alleles are efficiently expressed by synovial fibroblasts is germane to this hypothesis. To address this, cultured fibroblast-like synoviocytes (cFLS) were analyzed for constitutive and interferon (IFN)-gamma-induced expression of specific DRB alleles and class II-associated cochaperones. IFN-gamma induction of invariant chain, DM, and DR molecules was observed in all cFLS, but expression of specific DR allotypes was variable. Interestingly, DM-modulated epitopes on RA-associated DR molecules were either absent or delayed, despite strong DM expression and a paucity of major histocompatibility complex/class II-associated invariant chain peptide complexes. Altered expression of specific peptide-dependent epitopes on RA-associated HLA-DR molecules suggests differences in antigen presentation by cFLS, which may have implications for the immunopathogenesis of RA.

The genetic polymorphism of human factor H (beta 1H) was investigated by a combination of isoelectrofocusing and immunoblotting. This simple method is reliable and economical. The allelic frequencies in the Newfoundland population were estimated to be 0.597 and 0.403 for FH*1 and FH*2, respectively (129 individuals typed). No association of factor H types with rheumatoid arthritis was found (111 patients typed).

The HLA-DR4 association with rheumatoid arthritis (RA) was revealed in several pioneering observations by Stastny and others between 1974 and 1980 [1]. It is interesting that even in those early days there was an awareness that DR4 was not just associated with RA but was associated with severity of RA, as will be discussed later. As knowledge of the HLA system advanced and as further studies of RA were undertaken it became evident that the HLA association was by no means straightforward. For example, when it was found that DR4 was supertypic to a series of alleles - the subtypes of DR4 - it was noted that only a few of them were associated with RA; indeed one (DwlO or DRB1*0402) actually appeared to be protective. Later DR1 and DR14 were associated in some studies and DR10 was prominent in others. This confusing situation was considerably clarified when Gregersen et al. in 1987 [2] put forward the “shared epitope hypothesis”. These authors realised, from examination of the amino-acid sequence data that the alleles which were associated with RA all had a similar sequence in the beta chain, QKRAA or QRRAA at positions 70-74. This unifying hypothesis showed that the closest association between HLA and RA is with the shared sequence which lies on the edge of the MHC groove midway along one of its alpha helices. This is referred to as the “shared epitope”. The epitope concept leads into the purpose of this report which is to describe a series of monoclonal antibodies to DR4 and some of its subtypes as well as to the shared epitope. As will be discussed later, these antibodies may be useful in determining prognosis in early cases of RA.

A C4 haplotype containing C4*A6 without C4*B1 is described. It occurred in the MHC haplotype HLA-A1, Cw5, Bw44, C2*1, BF*S, C4*A6BQO, DR3, GLO 2. This haplotype was observed in five of eight siblings, including the propositus who was in renal failure. The C4A6 was not haemolytically active and this new haplotype is therefore of particular interest since it is functionally equivalent to the rare C4-deficient haplotype C4*AQOBQO.

Hedgehog serum proteins were studied by physical, chemical and immunological methods. The paper electrophoretic and immunoelectrophoretic patterns did not differ greatly from those of human serum. In paper electrophoresis two beta-bands were found, the beta2-band being the most conspicuous. In the immunoelectrophoretic pattern, the form of the “rapid” lipoprotein-line was found to vary with temperature and duration of storage of serum. Autoradiography showed transferrin in hedgehog serum to be a beta2-globulin. Antibody activity was found in two different fractions after gel filtration or ultracentrifugation of serum, probably representing antibodies of the 19S and 7s types.

1. 1. Hedgehog IgG2 was shown to have a hexose content of 1·05 per cent and a total carbohydrate content of 2·00 per cent. 2. 2. Papain digestion of IgG2 yielded F(ab) 2 Fab and Fc depending on the conditions. Digestion in the presence of 0·1 M cysteine destroyed the Fc fragment. 3. 3. Hedgehog IgG1 induced reversed passive cutaneous anaphylaxis in guinea-pigs. The results with IgG2 were inconclusive. 4. 4. Hedgehog IgG2 bound staphylococcal protein A (Fc binding) while IgG1 did not.

1. 1. Antibodies of IgM class reacting with rabbit red cells were shown to be present in serum from non-immunized hedgehogs. 2. 2. Antibodies of IgM, IgG1 and IgG2 class reacting with rabbit red cells were shown to be present in serum from hedgehogs immunized with the serum sickness antigen (sheep red cells). 3. 3. Antibody activity to rabbit red cells was not demonstrated in hedgehog IgA.

The phagocytosis and intracellular killing of Staphylococcus aureus by humans granulocytes in the presence of immunoglobulin preparations have been examined. Isolated IgG from pooled human serum induced phagocytosis and intracellular killing of bacteria. F(ab')2 fragments had no significant effect, indicating that the Fc piece of the IgG molecule is of importance not only for the phagocytosis but also for the intracellular killing of bacteria. Isolated IgM stimulated the phagocytosis to a minor extent, with no enhancement of the bactericidal activity.

We found the rare properdin factor B(Bf) variant F1 to be present in 11% of 72 patients suffering from insulindependent diabetes (IDDM) compared with 2% among 150 normal controls. BfF1 thus confers a relative risk for IDDM of 5.55. All eight patients and three controls who were BfF1 positive were also HLA-B18 positive, reflecting the strong linkage disequilibrium between these two factors. We suggest that BfF1 marks a ‘diabetogenic’ B18-bearing HLA haplotype. Studies of unselected families with one or more affected members suggest that the B18, BfF1 does not necessarily segregate with IDDM phenotype. This study provides further evidence for the genetic heterogeneity of IDDM.

Serum IgG, IgA, and IgM concentrations were measued in 120 members of a family with 33 cases of Dystrophia myotonica (Dm) and 27 members who were "possibly affected". The Dm individuals had significantly lower serum concentrations of IgG and IgA (P

The fourth component of complement (C4) has two classes of protein, C4A and C4B, both of which have many allelic forms. The serological determinants Rodgers (Rg1, Rg2) and Chido (Ch1, Ch2, Ch3) are generally associated with C4A and C4B, respectively. The C4B3 allotype has been detected in a single Canadian family that expresses a novel Ch phenotype, Ch:−1, 2, −3. There was no information for the Rg determinants, as the C4A * 2B * 3 haplotype would normally express Rg on the C4A protein. Other C4B3 allotypes in informative families have different Ch phenotypes, and the relationships of these within extended major histocompatibility complex haplotypes are discussed in this paper.

Sera from 305 individuals were typed for factor I, and a new variant, tentatively designated FI* C, was found. All other samples were FIB except for seven samples from Chinese that were of the FI AB phenotype. This suggests that polymorphism of factor I may be rare in Caucasians.

1. 1. Hibernating hedgehogs lysed intracardially injected foreign red cells slower than did non-hibernating hedgehogs. 2. 2. Ten out of nineteen hibernating hedgehogs immunized with sheep red cells formed antibody during hibernation. The latent period was at least 3 weeks. 3. 3. Two hedgehogs immunized twice started to produce antibodies after termination of hibernation. 4. 4. The antibodies formed during hibernation were predominantly of mercaptoethanol sensitive type.

1. 1. The concentration of IgG2 in serum of non-hibernating hedgehogs was fairly constant, 16 mg/ml. During hibernation the concentration fell steadily to reach the lowest value in March–April and then rose again after termination of hibernation. 2. 2. The mean decrease in serum concentration of IgG2 in two hibernating animals studied more closely was 0·05 mg/ml per day. 3. 3. The half-life of IgG2 in non-hibernating hedgehogs was 2·2 days. The half-life was prolonged to as much as 40 days in hibernating animals.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2–1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2* 1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B*2 whilst the Bw22 haplotypes mostly carry C4A*4, C4B*4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2*2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2*2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.