Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age

Virginia S Baker¹^,7 , Godwin E Imade² , Norman B Molta^{^}³ , Pallavi Tawde¹ , Sunday D Pam² , Michael O Obadofin² , Soloman A Sagay² , Daniel Z Egah² , Daniel Iya² , Bangmboye B Afolabi⁴ , Murray Baker⁵ , Karen Ford⁶ , Robert Ford⁶ , Kenneth H Roux¹ and Thomas CS Keller III¹

¹Department of Biological Science, Florida State University, Tallahassee, Florida, USA

²Jos University Teaching Hospital and Medical School, Jos, Nigeria

³Jos University, Jos, Nigeria

⁴Nigerian Institute of Medical Research, Yaba, Nigeria

⁵Jackson Hospital, Marianna, FL, USA

⁶World Health Mission, Pittsburgh, Pennsylvania, USA

⁷Chipola College, Marianna, FL 32446, USA

author email corresponding author email^Deceased

Malaria Journal 2008, 7:41doi:10.1186/1475-2875-7-41


Published:	29 February 2008

Abstract

Background

In Plasmodium falciparum-infected children, the relationships between blood cell histopathology, blood plasma components, development of immunocompetence and disease severity remain poorly understood. Blood from Nigerian children with uncomplicated malaria was analysed to gain insight into these relationships. This investigation presents evidence for circulating neutrophil extracellular traps (NETs) and antinuclear IgG antibodies (ANA). The presence of NETs and ANA to double-stranded DNA along with the cytokine profiles found suggests autoimmune mechanisms that could produce pathogenesis in children, but immunoprotection in adults.

Methods

Peripheral blood smear slides and blood samples obtained from 21 Nigerian children under six years of age, presenting with uncomplicated malaria before and seven days after initiation of sulphadoxine-pyrimethamine (SP) treatment were analysed. The slides were stained with Giemsa and with DAPI. Levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF, CRP, and IL-6, select anti-inflammatory cytokines TGF-β and IL-10, and ANA were determined by immunoassay.

Results

The children exhibited circulating NETs with adherent parasites and erythrocytes, elevated ANA levels, a Th2 dominated cytokine profile, and left-shifted leukocyte differential counts. Nonspecific ANA levels were significant in 86% of the children pretreatment and in 100% of the children seven days after SP treatment, but in only 33% of age-matched control samples collected during the season of low parasite transmission. Levels of ANA specific for dsDNA were significant in 81% of the children both pre-treatment and post treatment.

Conclusion

The results of this investigation suggest that NET formation and ANA to dsDNA may induce pathology in falciparum-infected children, but activate a protective mechanism against falciparum malaria in adults. The significance of in vivo circulating chromatin in NETs and dsDNA ANA as a causative factor in the hyporesponsiveness of CpG oligonucleotide-based malaria vaccines is discussed.