An array of pro-and anti-inflammatory mediators of the innate immune system was analyzed in stool, urine, and rectal mucosa samples from adults and children with shigellosis to better understand their role in recovery from and in the immunopathogenesis of the disease. Increased concentrations of lactoferrin (Lf), myeloperoxidase (MPO), prostaglandin E 2 , and leukotriene B 4 (LTB 4 ) in stool during acute shigellosis in both children and adults indicated that activated cells of the innate defense system at the mucosal site were secreting the mediators. Increased concentration of MPO and 8-iso-prostaglandin F 2␣ and lower levels of superoxide dismutase (SOD) activity in stool during acute Shigella infection suggested increased formation of reactive oxygen species, free radical-catalyzed peroxidation of membrane lipids, and decreased scavenging of the reactive oxygen radicals. In children, lower expression of SOD in tissue with severe inflammation and lower levels of SOD activity in stool for longer periods compared to adults may further worsen the tissue damage and predispose the children to a lowered defense. Both adult and pediatric patients had significantly higher expression of inducible nitric oxide synthase (iNOS) in the rectum with severe inflammation, compared to that seen with mild inflammation, accompanied by persistently up-regulated iNOS mRNA, reflecting increased production of nitric oxide at the local site. However, in contrast to adults, reduced urinary nitrate levels in pediatric patients during acute shigellosis suggested lower production of nitric oxide in the renal compartment.

We hypothesized that increased susceptibility to Shigella infection, increased severity of disease and high mortality in children compared with adults were consequences of insufficient adaptive immune responses. Antigen-specific immune responses were studied in paediatric patients (n 38, 2±10 years) with shigellosis and compared with those of adult patients (n 30, 18±45 years). Peak frequencies of antigen (invasion plasmid coded antigen B, Ipa-B; lipopolysaccharide, LPS)-specific immunoglobulin (IgM)-antibody secreting cells (ASC) were seen within 3±5 days after the onset of diarrhoea in children, while peak IgA-and IgG-ASCs were obtained 8±10 days later in line with adults. Antigen-specific ASC responses in children ranged between 2 and 4% of the total ASC responses, in contrast to 8±15% in adults. The kinetics of LPS-specific IgG subclass titres was different in younger children (2.5±5 years) (IgG1 > IgG2 > IgG4 > IgG3) compared with in older children (6±8 years) (IgG2 > IgG1 >IgG3 > IgG4) and adults. Secretory IgA levels in stool peaked 8±10 days after onset in both adults and children. However, a rapid induction of stool LPS-specific IgA, IgA1 and IgA2 occurred in adult patients within 3±5 days of onset, while in children, this was delayed by 8±10 days. Similarly, higher number of tumour necrosis factor (TNF)-a and interferon (IFN)-g expressing cells in vitro were seen in adult patients in response to antigens (LPS and Ipa-B) in the acute stage in contrast to paediatric patients. Thus, paediatric patients with shigellosis have reduced and delayed adaptive immune responses compared with adult patients.

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