Agnes Kurniawan

T-cell activation and the balance of antibody isotypes in human lymphatic filariasis

Human filarial infection presents a spectrum of clinical states with two major poles: asymptomatic microfilaraemia and amicrofilaraemic chronic disease. Microfilaremia is associated with a Th1-type tolerance, and maximal IgG4 antibodies, while elephantiasis patients react across a broad range of immune parameters. In this review, Rick Maizels and his colleagues discuss recent advances in the immunology of human filariasis and present a summary of their latest studies in an endemic area of Indonesia.

Depression of Antigen-Specific Interleukin-5 and Interferon-γ Responses in Human Lymphatic Filariasis as a Function of Clinical Status and Age

In an area in which brugian filariasis is endemic, when cytokine levels were analyzed as a function of clinical status comparing those who were asymptomatic and amicrofilaremic with those who were microfilaremic, it was found that both interferon (IFN)-gamma and interleukin (IL)-5 were suppressed in microfilariae carriers (P < .01 and P < .001, respectively), but IL-4 was unabated. Age had a significant effect on cytokine production in both groups. In asymptomatic amicrofilaremic subjects, IL-4 production was high in young persons and decreased with age, whereas in microfilaremic subjects, IL-4 increased significantly with age. Conversely, IFN-gamma showed a tendency to increase with age in asymptomatic amicrofilaremic subjects but not in microfilaremic subjects. IL-5 decreased significantly with increasing age in both asymptomatic amicrofilaremic and microfilaremic groups. These results indicate that the length of exposure to and infection with filarial parasites can each exert a substantial effect on the cytokine response profiles of host T cell populations.

Intestinal parasitic infections in HIV/AIDS patients presenting with diarrhoea in Jakarta, Indonesia.

We investigated the occurrence of intestinal parasites in Indonesian HIV/AIDS patients with chronic diarrhoea prior to administering antiretroviral therapy. The influence of age, CD4(+) cell count and season on parasite occurrence was also studied. In total, 318 unconcentrated stool samples were analysed using Lugols iodine and modified acid fast staining to detect intestinal coccidia. Most samples (94.5%) were from males aged 21-40 years with CD4(+) counts < or = 50 cells/mm(3). Parasites were found in 84.3% of samples (single species infections, 71.4%; polyparasitism, 12.9%), with protozoan pathogens occurring most commonly. Cryptosporidium (4.9%), Cyclospora cayetanensis (4.5%) and Giardia duodenalis (1.9%) were the most frequent single infections, but Blastocystis hominis (72.4%) was the most commonly occurring protist. Cryptosporidium and C. cayetanensis occurred in 11.9% and 7.8% of all (single and mixed) infections. The most common co-infection was with B. hominis and Cryptosporidium (6.3%). Intestinal protozoan pathogens were detected more frequently in cases with CD4(+) counts < or = 200/mm(3). No seasonal influence was determined for Cryptosporidium, C. cayetanensis or B. hominis, but gross seasonal disturbances may have influenced our findings. Intestinal parasites should be looked for routinely in this group of individuals and should be treated to reduce complications and the likelihood of transmission.

Specific T cell unresponsiveness in human filariasis: diversity in underlying mechanisms

In an attempt to overcome T cell unresponsiveness to filarial antigens, 65 individuals belonging to the three clinical groups of elephantiasis patients, microfilaraemics, and asymptomatic amicrofilaraemics who exhibited unresponsiveness to Brugia malayi adult worm antigen (BmA) were studied. Peripheral blood mononuclear cells were co‐cultured with antigen and one of the following reagents that have been reported to be effective in reconstituting T cell proliferation: interleukin‐2 (IL‐2), interleukin‐7 (IL‐7), anti‐interleukin‐4, anti‐interleukin‐10, anti‐CD2, anti‐CD27, anti‐CD28, indomethacin, phorbol myristate acetate (PMA), or calcium ionophore (A23I87). We were able to overcome antigen‐specific unresponsiveness in only a minority of the individuals studied. Co‐culture with IL‐2, IL‐7, indomethacin and PMA were the only conditions which resulted in enhanced proliferation to BmA in these individuals. In general, unresponsiveness in elephantiasis patients was easier to reverse than in other clinical groups: in 50% of elephantiasis patients, in 12.5% of microfilaraemics and in 20% of asymptomatic amicrofilaraemics. The results indicate that more than one distinct immunological mechanism may account for the antigen‐specific unresponsiveness in individuals exposed to and infected with brugian filariasis.

HLA and elephantiasis in lymphatic filariasis.

Lymphatic filariasis presents a spectrum of manifestations with infection-free asymptomatics at one end and elephantiasis at the other. In order to determine if any HLA antigens are associated with the development of elephantiasis, we compared the HLA frequencies in 55 elephantiasis patients with those in 40 controls consisting of individuals older than 45 years of age without any signs of elephantiasis. The only significant difference in class I antigen frequencies was observed for B27, which was present in 11% of the patients and absent in the controls. More differences were observed in HLA class II antigen frequencies. Both DR3 and the 2B3 epitope (on DQ6, DQ8, and DQ9 molecules) were significantly decreased in patients with elephantiasis whereas the DQ5 frequency was significantly higher in patients than in controls. Analysis of specific antibody isotype profiles revealed that DQ5-positive individuals had increased levels of antifilarial IgG3, an isotype known to be involved in tissue damage. These data suggest that HLA class II genes may control the course of Brugian filariasis by influencing the T-cell-dependent antibody repertoire.

Most of the Response Elicited against Wolbachia Surface Protein in Filarial Nematode Infection Is Due to the Infective Larval Stage

Immune responses to the intracellular Wolbachia bacteria of filarial nematodes are thought to contribute to the pathologic process of filarial infection. Here, we compare antibody responses of subjects living in an area where lymphatic filariasis is endemic with antibody responses elicited in a murine model of filarial infection, to provide evidence that the infective larval stage (L3), not adult nematodes, are the primary inducer of responses against Wolbachia. In human subjects, antibody responses to Brugia malayi Wolbachia surface protein (WSP) are most often correlated with antibody responses to the L3 stage of B. malayi. Analysis of anti-WSP responses induced in mice by different stages of the rodent filariae Litomosoides sigmodontis shows that the strongest anti-WSP response is elicited by the L3 stage. Although adult filarial nematode death may play a role in the generation of an anti-WSP response, it is the L3 stage that is the major source of immunogenic material, and incoming L3 provide a continual boosting of the anti-WSP response. Significant exposure to the endosymbiotic bacteria may occur earlier in nematode infection than previously thought, and the level of exposure to infective insect bites may be a key determinant of disease progression.

Cryptosporidium species from human immunodeficiency–infected patients with chronic diarrhea in Jakarta, Indonesia

PURPOSE Cryptosporidium is an opportunistic parasite that manifests as chronic and severe diarrhea in the immune-compromised subject. We investigated the species of Cryptosporidium to understand the epidemiology, mode of transmission, response to treatment, and prevention. METHODS Polymerase chain reaction/restriction fragment length polymorphism of the 18 S rRNA gene and sequencing were performed on 41 Cryptosporidium-positive stools from 36 patients with HIV AIDS, which comprised 36 pretreatment stools and 5 stools after treatment with Paromomycin. RESULTS C. hominis, C. meleagridis, C. felis, and C. parvum were detected; 28 of 36 (77.7%) patients were infected with C. hominis and two (5.5%) patients with multiple species of Cryptosporidium. Treatment with Paromomycin resulted in different outcomes, perhaps because patients harbored other intestinal parasitic infections. CONCLUSIONS Multiple infection with various Cryptosporidium species in the presence of other intestinal parasites occurs in patients with HIV AIDS suffering from chronic diarrhea who are severely immune-compromised. Common transmission of Cryptosporidium is anthroponotic.

Immune responses to filarial parasites

Filarial nematode parasites are long-lived organisms which are responsible for one of the major tropical diseases. Their ability to survive may be related to the antigen-specific anergic state observed in carriers of the parasite. Severe disease symptoms are associated with the breakdown of anergy. Different stages of the parasite life cycle are anti-genetically distinct, and a state of concomitant immunity is therefore possible which prevents superinfection. The evidence for these conclusions is discussed, in the context of the need for an effective vaccine against filarial parasites which will avoid any risk of increasing disease severity.

The Secreted Triose Phosphate Isomerase of Brugia malayi Is Required to Sustain Microfilaria Production In Vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections.

Presentation, etiology, and outcome of brain infections in an Indonesian hospital: A cohort study

Background Little detailed knowledge is available regarding the etiology and outcome of CNS infection, particularly in HIV-infected individuals, in low-resource settings. Methods From January 2015 to April 2016, we prospectively included all adults with suspected CNS infection in a referral hospital in Jakarta, Indonesia. Systematic screening included HIV testing, CSF examination, and neuroimaging. Results A total of 274 patients with suspected CNS infection (median age 26 years) presented after a median of 14 days with headache (77%), fever (78%), seizures (27%), or loss of consciousness (71%). HIV coinfection was common (54%), mostly newly diagnosed (30%) and advanced (median CD4 cell count 30/µL). Diagnosis was established in 167 participants (65%), including definite tuberculous meningitis (TBM) (n = 44), probable TBM (n = 48), cerebral toxoplasmosis (n = 48), cryptococcal meningitis (n = 14), herpes simplex virus/varicella-zoster virus/cytomegalovirus encephalitis (n = 10), cerebral lymphoma (n = 1), neurosyphilis (n = 1), and mucormycosis (n = 1). In-hospital mortality was 32%; 6-month mortality was 57%. The remaining survivors had either moderate or severe disability (36%) according to Glasgow Outcome Scale. Conclusion In this setting, patients with CNS infections present late with severe disease and often associated with advanced HIV infection. Tuberculosis, toxoplasmosis, and cryptococcosis are common. High mortality and long-term morbidity underline the need for service improvements and further study.