Associations Between Secretory Immunoglobulin A and Social Network Structure.

PURPOSE: This study investigates the social determinants of health by examining how mucosal immunity is associated with the patterning of social connections in a network. Studies have suggested that social networks have biological underpinnings, but investigations at the scale of networks, rather than individuals, have remained elusive. We integrate salivary bioscience methods with advanced social network modeling to explore the association between salivary secretory immunoglobulin A (SIgA), a key component of mucosal immunity, and social network structure. METHOD: Friendship network data and saliva samples (later assayed for SIgA) were obtained from a large mixed-gender social organization (n = 155, 55% female, M age = 19.5 years). RESULTS: Exponential random graph modeling revealed that SIgA levels were positively associated with reporting more friendship ties with community members (i.e., social network activity), after controlling for other processes associated with network structure including preference to befriend others of the same age, gender, and extraversion, increased network popularity of agreeable individuals and those with lower levels of perceived stress, as well as network structural and organizational processes. CONCLUSION: By examining a wider range of associations between SIgA and network structure, we pinpoint that SIgA is positively associated with respondent's sociability. Our findings are consistent with social integration theories linking social relationships to health and highlight the role of humoral immunity as a possible mediator of these associations.

Coincident linkage of fasting plasma insulin and blood pressure to chromosome 7q in hypertensive hispanic families.

BACKGROUND: Insulin resistance (IR) and hyperinsulinemia are phenotypically associated with hypertension. We have previously provided evidence that blood pressure (BP) and IR cosegregate in Hispanic families, suggesting that this association has a genetic component. In the present study, we provide further support for the hypothesis of a genetic basis for the BP-IR relationship from a genetic linkage study. METHODS AND RESULTS: A 10-cM genome scan was conducted in 390 Hispanic family members of 77 hypertensive probands. Detailed measurements of BP, glucose, insulin levels, and insulin sensitivity (euglycemic clamp) were performed in adult offspring of probands. Multipoint variance component linkage analysis was used. A region on chromosome 7q seemed to influence both IR and BP. The greatest evidence for linkage was found for fasting insulin (lod score=3.36 at 128 cM), followed by systolic BP (lod score=2.06 at 120 cM). Fine mapping with greater marker density in this region increased the maximum lod score for fasting insulin to 3.94 at 125 cM (P=0.00002); lod score for systolic BP was 2.51 at 112 cM. Coincident mapping at this locus also included insulin sensitivity measured by the homeostasis assessment model (HOMA) and serum leptin concentrations. Insulin sensitivity by euglycemic clamp did not map to the same locus. CONCLUSIONS: Our results demonstrate that a major gene determining fasting insulin is located on chromosome 7q. Linkage of BP, HOMA, and leptin levels to the same region suggests this locus may broadly influence traits associated with IR and supports a genetic basis for phenotypic associations in IR syndrome.

The role of MHC class I glycoproteins in the regulation of induction of cell death in immunocytes by malignant melanoma cells.

A deranged expression of MHC class I glycoproteins, characteristic of a variety of malignancies, contributes to the ability of cancer to avoid destruction by T cell-mediated immunity. An abrogation of the metastatic capacity of B16 melanoma cells has been achieved by transfecting an MHC class I-encoding vector into class I-deficient B16 melanoma clones [Gorelik, E., Kim, M., Duty, L. & Galili, U. (1993) Clin. Exp. Metastasis 11, 439-452]. We report here that the deranged expression of class I molecules by B16 melanoma cells is more than a mere acquisition of the capacity to escape immune recognition. Namely, cells of the B16 melanoma prompted splenic lymphocytes to commit death after coculture. However, a class I-expressing and nonmetastatic CL8-2 clone was found to be less potent as an inducer of apoptosis than class I-deficient and metastatic BL9 and BL12 clones. Both Thy1.2(+) and Thy1.2(-) splenocytes underwent cell death when exposed to the class I-deficient BL9 clone. A proportion of CD4(+) and CD8(+) cells among splenocytes exposed to the BL9 clone was lower than that observed in a coculture with cells of the CL8-2 clone. Consistently, none of the melanoma clones studied produced a ligand to the FAS receptor (FAS-L). Thus, our results provide evidence that (i) the production of FAS-L may not be the sole mechanism by which malignant cells induce apoptosis in immunocytes, and (ii) absence of MHC class I glycoproteins plays an important role in preventing the elimination of potential effector immunocytes by tumor cells.

A genome-wide search identifies potential new susceptibility loci for Crohn's disease.

Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.

Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn's disease, but not in ulcerative colitis.

In the Western world, chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC) [Targan, S.R. and Shanahan, F. (1994). In Retford, D.C (ed.), Inflammatory Bowel Disease: From Bench to Bedside. Williams and Wilkins, Baltimore]. Genetic epidemiological studies, the occurrence of rare syndromes associated with IBD, and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD [Yang, H.-Y. and Rotter, J.I. (1995) In Kirsner, J.B. and Shorter, R.G. (eds). Genetic Aspects of Idiopathic Inflammatory Bowel Disease. Williams and Wilkins, Baltimore, pp.301-331]. Recently, a genome-wide search on European families with multiple affected members with CD identified a putative susceptibility locus in the centromeric region of chromosome 16 [Hugot, J.-P. et al. (1996) Nature, 379, 821-823]. We have now tested this region in an independent set of US families, confirmed that this region is likely to contain a gene predisposing to CD, and further refined the chromosomal location of this gene. Most importantly with respect to this locus, our data also seem to indicate that there is heterogeneity both within the CD group, and between the CD and UC groups with respect to this locus. The susceptibility locus appears to be involved only in non-Jewish CD sibpairs and not in our Ashkenazi Jewish CD sibpairs. Additionally, we have tested sibpairs having either only UC or both UC and CD for involvement of this locus, and have found no evidence that this region predisposes to IBD in these patients.

Posterior chamber intraocular lenses: long-term results in pediatric cataract patients.

Major problems in pediatric cataract patients include noncompliance with contact lenses resulting in amblyopia. Advances in intraocular cataract surgery have provided a better environment to perform intraocular lens (IOL) implantation in children. We prospectively analyzed the results of 34 consecutive pediatric patients who underwent cataract removal and insertion of an IOL. Operative technique performed was posterior scleral beveled or frown incision and IOL endocapsular fixation. Subgroups included 10 eyes with traumatic cataract, and 24 eyes with developmental cataracts. Six patients had bilateral IOLs. Data presented in each subgroup included initial and final visual acuity, age, sex, type of cataract, A and B scan biometry, early and late postoperative complications, time of YAG capsulotomy, postoperative refractive correction, and state of binocular vision. Preoperative visual acuity ranged from 20/70 to light perception. The success rate for postoperative visual acuity of 20/40 or better occurred in 29 of 34 eyes, or 85.3%. In the traumatic cataracts, 8 of 10 eyes (80%) obtained 20/40 vision or better. In developmental cataracts, 21 of 24 eyes (88%) achieved visual acuity of 20/40 or better. Amblyopia (three patients) or macular scar (two patients) accounted for reduced visual acuity in the five eyes with vision less than 20/40. Early complications included posterior synechiae and lens deposits. The primary late complication was opacification of the posterior capsule in 18 of 34 eyes. The average time for YAG capsulotomy post-cataract removal was 17 months. None of the 28 patients (34 eyes) developed glaucoma, IOL dislocation, or other significant postoperative problems related to IOL insertion.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families.

The role of HLA class II alleles in genetic predisposition to insulin dependent diabetes mellitus (IDDM) was examined by PCR/oligonucleotide probe typing of 42 Mexican-American IDDM families derived from Hispanic Caucasians and Native Americans. All high risk haplotypes (HLA-DR3 and DR4) were of European origin while the most strongly protective haplotype (DRB1*1402) was Native American. Of the 16 DR-DQ DR4 haplotypes identified, only those bearing DQB1*0302 conferred risk; the DRB1 allele, however, also markedly influenced IDDM risk. The general pattern of neutral and protective haplotypes indicates that the presence of Asp-57 in the HLA-DQ beta chain does not confer IDDM protection per se and indicates that both DRB1 and DQB1 influence IDDM susceptibility as well as protection.

Distinct associations of HLA class II genes with inflammatory bowel disease.

BACKGROUND: There are relatively few studies of HLA class II association either with Crohn's disease (CD) or ulcerative colitis (UC). The few available association studies have been carried out by serological techniques, and the results from these studies are inconclusive. METHODS: The association between HLA class II genes was studied using molecular genotyping in combination with allele-specific oligonucleotide hybridization by polymerase chain reactions. RESULTS: In UC (n = 74), we observed a positive association with the HLA DR2 allele (P = 0.008) and negative associations with the DR4 (P = 0.018) and DRw6 (P = 0.028) when compared with ethnically matched controls (n = 77). No associations were observed with any DQ alleles. In contrast, in CD (n = 95) we observed a positive association with the combination of DR1 and DQw5 alleles (P = 0.021). Furthermore, stratifying DR1 and DQw5 alleles indicated that neither allele was independently associated with CD, suggesting that the association was with the haplotype rather than either of the alleles individually. A suballele of DQw5, DQB1*0501, contributed this haplotypic association (P = 0.012). CONCLUSIONS: DR and DQ molecules firmly separate UC and CD on genetic grounds, suggesting that the contribution of the HLA class II genes to the disease susceptibility is quite different for the two disorders.

Biochemical characterization of a pedigree with mitochondrially inherited deafness.

A large kindred with a predicted 2-locus inheritance of sensorineural deafness, caused by the combination of a mitochondrial and an autosomal recessive mutation, was examined at the biochemical level. Because of the mitochondrial inheritance of this disease, we looked for defects in the oxidative phosphorylation Complexes I, III, IV, and V, the 4 enzymes that include all of the 13 mitochondrially encoded polypeptides. Biosynthetic labelling of lymphoblastoid cells from deaf patients, unaffected siblings, and an unrelated control showed no difference in size, abundance, rate of synthesis, or chloramphenicol-sensitivity of the mitochondrially encoded subunits. Since overall mitochondrial protein synthesis appears normal, these results suggest that the mitochondrial mutation is unlikely to be in a tRNA or rRNA gene. No change in enzymatic levels was seen in lymphoblastoid mitochondria of the deaf patients, compared to unaffected sibs and controls, for Complexes I and IV. Both affected and unaffected family members showed an increase in Complex III activity compared to controls, which may reflect the mitochondrial DNA shared by maternal relatives, or be due to other genetic differences. Complex V activity was increased in deaf individuals compared to their unaffected sibs. Since the family members share the presumptive mitochondrial mutation, differences between deaf and unaffected individuals likely reflect the nuclear background and suggest that the autosomal recessive mutation may be related to the increase in Complex V activity. These biochemical studies provide a guide for sequence analysis of the patients' mitochondrial DNA and for linkage studies in this kindred.

Effects of herpes simplex virus on induced cell-mediated cytotoxicity in neonates and adults.

Deficient cellular cytotoxic mechanisms are present in neonates, contributing to their increased susceptibility to certain viruses, notably herpes simplex virus (HSV). Significant lymphokine-activated killer (LAK) cell activity has been described in cord blood, suggesting a possible role for LAK and/or interleukin-2 (IL-2) therapy in newborns with serious viral infections. The effect of HSV (type 1) on the activation of cord versus adult LAK cells was investigated by adding virus (multiplicity of infection, MOI = 10) to cells that had been previously incubated for 4-6 days with IL-2 (50-100 U/ml). The cells were then tested 24 h after virus exposure for cytotoxic activity against 51Cr-labelled K562 and Raji target cells. HSV inhibited LAK cytotoxicity of adult cells against K562 by 44% (72 +/- 2.4%, SEM; specific lysis to 40 +/- 6.2%, n = 15) and by 62% against Raji targets (50 +/- 5.6 to 19 +/- 4.4%). A similar degree of inhibition was observed for cord cells against K562 (76 +/- 2.0 to 46 +/- 5.3%) and Raji (60 +/- 4.6 to 24 +/- 6.2%). The degree of inhibition was correlated with the dose of virus in dose-response experiments. Inhibition was also noted with irradiated (10,000 rad) but not with heat-inactivated (56 degrees C for 60 min) virus. No inhibition was found when virus was added directly to the cytotoxic assay or when virus was added at the initiation or end of culture of cells with IL-2 (i.e. day 0 or day 5-7). In contrast, HSV stimulated cytotoxic activity against both the natural killer (NK)-sensitive (K562) and NK-resistant (Raji) targets in cells not incubated with IL-2. The cytotoxicity of adult cells incubated with infectious HSV (MOI = 10) for 5-7 days increased from 5.5 +/- 1.9% in the absence of virus to 25 +/- 6.0% against K562 in the presence of virus and from 3.5 +/- 1.0 (no virus) to 16 +/- 4.3% (with virus) against Raji targets (n = 8). The cytotoxicity of cord cells was also stimulated, but to a lesser degree. Irradiated virus also stimulated cytotoxic activity but to a lesser degree in cord cells. Virus-induced nonspecific cytotoxicity may represent an important component of the host's antiviral defense that is present at birth, but somewhat diminished compared to normal adults.

Surgical treatment of Duane's syndrome.

Nineteen patients undergoing treatment for Duane's syndrome are reported. The patients were treated with appropriate horizontal muscle recession in order to relieve abnormal head position or a significant tropia in primary position. Success rate in eliminating the abnormal head position was 79% while 100% were significantly improved. No overcorrections occurred despite large recessions. Retraction in adduction was reduced in each case. Motility of the eye was not increased following recession and in no case was fusion ability or stereopsis affected. The elimination of abnormal head position appears to be stable for periods up to 8.75 years. Postoperatively, patients obtained approximately 30 degrees of binocular visual field including primary position. Other surgical techniques in treating Duane's syndrome are discussed.

Pediatric aphakic glaucoma.

Three cases of pediatric open-angle aphakic glaucoma are presented. These patients had congenital cataracts extracted by the extracapsular techniques of phacofragmentation or irrigation and aspiration. Each required a secondary membranectomy and had development of glaucoma six to 25 months after cataract extraction. Surgical therapy was required in each case of glaucoma, and multiple procedures were necessary. Visual outcome in the involved eye was less than 20/400. The cause of the open-angle aphakic glaucoma is most likely secondary to damage to the trabecular meshwork initiated by uveitis and lens remnants. We urge ophthalmologists who perform pediatric cataract surgery to use phacofragmentation of the cataract and posterior capsule and anterior vitrectomy with vitrectomy instrumentation. This should reduce the incidence of secondary membranes and glaucoma. Ophthalmologists should be aware of this complication and the necessity of prolonged patient follow-up.