Diminished Monocyte Function in Microfilaremic Patients with Lymphatic Filariasis and Its Relationship to Altered Lymphoproliferative Responses

Abstract

Antigen-specific hyporesponsiveness to filarial antigens is a phenomenon observed in patent infection with lymph-dwelling filarial parasites of humans. This phenomenon has been attributed to a multitude of factors, one of which is altered monocyte function. To examine the role played by monocytes in filarial infection, we assessed the responses of monocytes obtained from normal and filarial parasite-infected individuals to both crude filarial antigen and purified recombinant filarial antigen WbSXP-1 and attempted to relate these to the altered lymphoproliferative responses seen in filarial infection. Monocytes from microfilaremic (MF) patients demonstrated an inability to respond to lipopolysaccharide compared to monocytes from endemic normal persons or from lymphedema patients. Indeed, interleukin 1␤ (IL-1␤) production was severely limited, a finding that did not extend to monocyte responses to filarial antigens. Serum from MF patients reduced adherence and spreading of normal monocytes, a finding not seen with serum from the other clinical groups. Interestingly, there was a significant correlation between the production of IL-1␤ and adherence. Moreover, the levels of spontaneous production of IL-1␤ correlated with high levels of spontaneous secretion of IL-10. The effects observed were not a result of diminished viability or alteration in the expression of the cell surface markers CD14 and HLA-DR. These data suggest that monocyte function is dampened in MF patients, a finding which could alter lymphoproliferative responses during patent infection.Understanding the induction of differentiated T-cell responses in helminth infections has been a major goal for parasite immunologists. The source of cytokines involved in the skewing of T-cell responses in helminth infections has been of particular interest, as the cytokine microenvironment is considered to be the most important factor influencing the differentiation of naive T cells and the generation of immunoregulatory cells (1,30,31,36,37). Among individuals with human lymphatic filariasis, those with patent infection (microfilaremic or antigenemic) exhibit parasite antigen-specific down-regulation of T-cell proliferation and gamma interferon production. These responses are different from those in patients with lymphedema/elephantiasis (mixed Th1/Th2 response) and infection-free endemic normal (EN) persons (predominant Th1 response to parasite antigen). The occurrence of filarial parasite-associated modulation of the immune response in microfilaremic patients is supported by extensive clinical (35,38,41) and animal (27) data. To date, however, no single mechanism can explain the modulatory effects of filarial infection in patients with patent infection.The induction and maintenance of Th2-type immune responses are based largely on studies with murine models showing that antigen affinity for the T-cell receptor (6), the dose or route by which antigen is administered (11,14), costimulatory molecule interactions (32, 49), the prevailing in vivo cytokine milieu (45),...

F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection

“…Studies in humans and animal models have demonstrated that immune inhibition extends to many arms of the immune response, including DC (33,46), macrophages/monocytes (12,47), and T cells (7,48), and that parasites secrete numerous molecules to aid in this task (45). These and other studies indicate that the mechanisms of filarial suppression differ according to the stage of the life cycle, and that patency is a turning point at which maximal suppression occurs (17,(25)(26)(27)(28).…”

“…There is clear evidence during human infection that APC function is compromised (11,12), and rodent models of filarial infection have demonstrated a variety of mechanisms by which filarial parasites immunosuppress their host (13)(14)(15)(16)(17)(18)(19). Mosquito-borne Brugia malayi L3 larvae are able to down-regulate expression of MHC class I and class II on human Langerhans cells and to inhibit their ability to activate T cells in vitro (20), whereas the same parasites, if injected into the murine peritoneal cavity, induce suppressive nematode-elicited macrophages (NeM) 3 that are able to block T cell proliferative responses (21).…”

Lymphoproliferative and Cytokine Responses to Cryptosporidium parvum in Patients Coinfected with C. parvum and Human Immunodeficiency Virus

“…According to the first method (29), subjects showing SI of Ͼ2 in response to CCA and Ͼ20 in response to PHA were considered subjects showing positive responses. In another method (13,25,26,27,29), median SI values between the different groups were compared as reported earlier for various infections including parasites.…”

Filaria-Induced Monocyte Dysfunction and Its Reversal following Treatment

“…Preparation of cRNA, hybridization, and scanning of the U133A arrays were performed according to the manufacturer's protocol (Affymetrix, Santa Clara, CA). Briefly, 2 to 4 g of RNA was converted into double-stranded cDNA by reverse transcription using a cDNA synthesis kit (SuperScript Choice; Life Technologies, Gaithersburg, MD) with an oligo(dT) 24 primer containing a T7 RNA polymerase promoter site added 3Ј of poly(T) (Genset Oligos, La Jolla, CA). After secondstrand synthesis, biotin-labeled cRNA was generated from the cDNA sample by an in vitro transcription reaction supplemented with the Bioarray high-yield RNA transcription labeling kit (Enzo, Farmingdale, NY).…”

“…Purified monocytes from filaria-infected patients have recently been shown to function less well, based on measurement of phagocytosis or spreading in response to a bacterial stimulus (24).…”