Ann E. Gordon

Cytokine responses and sudden infant death syndrome: genetic, developmental, and environmental risk factors

Despite the success of the campaigns to reduce the risk of sudden infant death syndrome (SIDS), it still remains the major cause of postneonatal mortality. The incidence of SIDS is higher among ethnic groups in which there are also high incidences of serious infectious diseases. The risk factors for SIDS parallel those for susceptibility to infection, and recent data have provided evidence to support the mathematical model of the common bacterial toxin hypothesis. One current hypothesis for the etiology of SIDS is that the deaths are a result of overwhelming proinflammatory responses to bacterial toxins; as in inflammatory responses to sepsis, cytokines, induced by bacterial toxins, cause physiological changes leading to death. The genetic, developmental, and environmental risk factors for SIDS are reviewed in relation to colonization by potentially harmful bacteria and the inflammatory responses induced in the nonimmune infant to microorganisms or their products.

The role of bacterial toxins in Sudden Infant Death Syndrome (SIDS)

There is increasing evidence for the involvement of bacterial toxins in some cases of sudden infant death syndrome (SIDS), particularly the pyrogenic toxins of Staphylococcus aureus. This had led to the hypothesis that some SIDS deaths are due to induction of inflammatory mediators by infectious agents or their products during a period in which the infant is unable to control these normally protective responses. The genetic, developmental and environmental risk factors identified for SIDS are assessed in relation to frequency or density of mucosal colonisation by toxigenic bacteria and their effects on induction and control of inflammatory responses to the toxins.

Proinflammatory Responses to Lipo-oligosaccharide of Neisseria meningitidis Immunotype Strains in Relation to Virulence and Disease

Inflammatory responses to lipo-oligosaccharide (LOS) contribute to the severity of meningococcal disease. Strains that express the L(3,7,9) LOS immunotypes are isolated from the majority of patients, but other immunotypes are isolated predominantly from carriers. Inflammatory responses elicited from a human monocytic cell line (THP-1) that had been pretreated with vitamin D3 (VD3) were compared after stimulation with purified LOSs from standard immunotype strains. The neutralizing effects of normal human serum and serum from mice immunized with strain B:2a:P1.5,2:L3 were compared. LOSs of immunotypes L3, L7, L8, and L9 induced significantly higher levels of tumor necrosis factor-alpha and interleukin-6, compared with other immunotypes. Normal human serum neutralized the proinflammatory responses to LOSs of all immunotypes tested. Immune mouse serum neutralized inflammatory responses against LOSs from immunotypes with epitopes cross-reactive with L(3,7,9) moieties. Antibodies found in normal human serum and immune mouse serum to the oligosaccharide, core, and lipid A moieties of meningococcal endotoxin contribute to neutralizing activity.

Making sense of the risk factors for sudden infant death syndrome (SIDS): infection and inflammation

Evidence from epidemiological and laboratory studies on sudden infant death syndrome (SIDS) has led to the following hypothesis. Some cases of SIDS are due to induction of in ̄ammatory mediators by infectious agents or their products during a period in which the infant is unable to control these normally protective responses. The genetic, developmental and environmental risk factors identi®ed for SIDS are assessed in relation to this hypothesis. # 2001 Lippincott Williams & Wilkins

Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ

Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-γ (IFN-γ) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-γ on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-γ responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-γ on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-γ responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-γ. THP-1 cells showed a dose dependent effect of IFN-γ on cytokine responses to endotoxin. For PBMC, IFN-γ enhanced interleukin (IL)-1β, IL-6, and tumor necrosis factor-α responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-γ. There was no effect of gender or genotype on IFN-γ responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.

Genetic and Environmental Factors Affecting TNF-α Responses in Relation to Sudden Infant Death Syndrome.

Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide polymorphism (SNP) associated with high levels of tumor necrosis factor-α (TNF-α) responses, TNF G-308A, in sudden infant death syndrome (SIDS) infants, SIDS and control parents, and ethnic groups with different incidences of SIDS; (2) the effects of two risk factors for SIDS, cigarette smoke and virus infection, on TNF-α responses; and (3) to assess effects of genotype, cigarette smoke, and gender on TNF-α responses to bacterial toxins identified in SIDS infants. TNF G-308A genotypes were determined by real-time polymerase chain reaction for SIDS infants from Australia, Germany, and Hungary; parents of SIDS infants and their controls; and populations with high (Aboriginal Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. Leukocytes from Caucasian donors were stimulated in vitro with endotoxin or toxic shock syndrome toxin-1 (TSST-1). TNF-α responses were measured by L929 bioassay (IU/ml) and assessed in relation to genotype, smoking status, and gender. There was a significantly higher proportion of the minor allele AA genotype among Australian SIDS infants (6/24, 24%) compared to 3/62 (4.8%) controls (p = 0.03). There were no significant differences in TNF-α responses by TNF G-308A genotypes when assessed in relation to smoking status or gender. Given the rarity of the TNF G-308A A allele in Caucasian populations, the finding that 24% of the Australian SIDS infants tested had this genotype requires further investigation and cautious interpretation. Although non-smokers with the AA genotype had higher TNFα responses to both TSST-1 and endotoxin, there were too few subjects with this rare allele to obtain statistically valid results. No effects of genotype, smoking, or gender were observed for TNF-α responses to these toxins.