FILARIAL-SPECIFIC ANTIBODY RESPONSE IN EAST AFRICAN BANCROFTIAN FILARIASIS: EFFECTS OF HOST INFECTION, CLINICAL DISEASE, AND FILARIAL ENDEMICITY WALTER G. JAOKO, PAUL E. SIMONSEN,* DAN W. MEYROWITSCH, BENSON B. A. ESTAMBALE, MWELE N. MALECELA-LAZARO, AND EDWIN MICHAEL Department of Medical Microbiology, and Institute of Tropical and Infectious Diseases, University of Nairobi, Nairobi, Kenya; DBL–Institute for Health Research and Development, Charlottenlund, Denmark; Department of Epidemiology, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark; National Institute for Medical Research, Dar es Salaam, Tanzania; Department of Infectious Diseases Epidemiology, Imperial College School of Medicine, London, United Kingdom Abstract. The effect of host infection, chronic clinical disease, and transmission intensity on the patterns of specific antibody responses in Bancroftian filariasis was assessed by analyzing specific IgG1, IgG2, IgG3, IgG4, and IgE profiles among adults from two communities with high and low Wuchereria bancrofti endemicity. In the high endemicity community, intensities of the measured antibodies were significantly associated with infection status. IgG1, IgG2, and IgE were negatively associated with microfilaria (MF) status, IgG3 was negatively associated with circulating filarial antigen (CFA) status, and IgG4 was positively associated with CFA status. None of the associations were significantly influenced by chronic lymphatic disease status. In contrast, IgG1, IgG2, and IgG4 responses were less vigorous in the low endemicity community and, except for IgG4, did not show any significant associations with MF or CFA status. The IgG3 responses were considerably more vigorous in the low endemicity community than in the high endemicity one. Only IgG4 responses exhibited a rather similar pattern in the two communities, being significantly positively associated with CFA status in both communities. The IgG4:IgE ratios were higher in infection-positive individuals than in infection- negative ones, and higher in the high endemicity community than in the low endemicity one. Overall, these results indicate that specific antibody responses in Bancroftian filariasis are more related to infection status than to chronic lymphatic disease status. They also suggest that community transmission intensity play a dominant but subtle role in shaping the observed response patterns. INTRODUCTION The contribution of parasite specific antibody responses to infection and chronic disease manifestations in lymphatic fil- ariasis still remains unclear. Early work in this area that fo- cused on antibody responses in microfilaremic individuals in comparison with individuals either with chronic lymphatic pa- thology or presumably exposed but displaying no outward signs of infection (so-called endemic normal individuals) sug- gested a differential expression of filarial-specific antibody responses in these patient categories. 1–3 In particular, these early studies suggested a dichotomy in the expression of spe- cific antibody responses between the categories, namely a high specific IgG4 response and IgG4:IgE ratio in microfila- remic individuals compared with a more prominent IgG1, IgG2, and IgG3 response in patients with elephantiasis and endemic normal individuals. These findings have been central to immunologic explanations for the pathogenesis of chronic filarial disease: that microfilaremic individuals are largely hy- poresponsive to filarial antigens as a result of carrying active infection while chronic pathology is the result of a subsequent gain of immune responsiveness to these antigens. A major problem with these investigations, however, has been the inability to accurately diagnose the infection status of individuals by using detection of microfilariae in blood samples. The biases introduced by inaccurate infection clas- sification in retarding a better understanding of the immuno- biology of filariasis have been highlighted by Freedman. 4 Re- cent studies in which patient classification was improved con- siderably using parasite antigen detection have shown that both cytokine responses, T cell proliferation, and specific hu- moral responses to filarial antigens may be more related to infection than to overt clinical manifestations. 4,5 These find- ings cast doubt on an immunologic etiology as a primary cause of chronic disease pathogenesis in filariasis and point to the critical need for accurate classification of infection status in any study attempting to determine the role of immune responses in the natural history of filarial infection and dis- ease. More recent studies have also highlighted the role that fi- larial endemicity or community transmission intensity may play in immune processes in filariasis. 6–11 Not only may spe- cific anti-filarial antibody responses be related to transmission intensity, but acquired immunity and immunopathologic re- sponses may also be functions of filariasis endemicity or level of parasite transmission. 10–13 Population dynamic studies of the stimulation and regulation of immune responses to para- sitic infection have furthermore highlighted the key role that nonlinear interactions of immune components with exposure intensity may play in regulating either a host protective re- sponse or immunologic unresponsiveness (tolerance) to para- sitic infection. 14–17 These findings suggest that in addition to infection or clinical status, anti-filarial immune responses in individuals are also related to the transmission intensity to which they are exposed in the community, a factor that thus clearly needs to be considered when investigating any asso- ciation between an immune component and clinical states of filariasis in individuals. The work presented here is part of a broader study of the immunoepidemiology of Wuchereria bancrofti infection in coastal East Africa. 11,18 In this report, we describe and evalu- ate the filarial-specific antibody responses from adults in two endemic communities differing in endemicity according to both parasitologic and clinical status in an attempt to define *Address correspondence to Paul E. Simonsen, DBL–Institute for Health Research and Development, Jaegersborg Alle 1D, 2920 Char- lottenlund, Denmark. E-mail: pesimonsen@dblnet.dk Am. J. Trop. Med. Hyg., 75(1), 2006, pp. 97–107 Copyright © 2006 by The American Society of Tropical Medicine and Hygiene 97