Quiescent Innate Response to Infective Filariae by Human Langerhans Cells Suggests a Strategy of Immune Evasion

Abstract

bFilarial infection is initiated by mosquito-derived third-stage larvae (L3) deposited on the skin that transit through the epidermis, which contains Langerhans cells (LC) and keratinocytes (KC), among other cells. This earliest interaction between L3 and the LC likely conditions the priming of the immune system to the parasite. To determine the nature of this interaction, human LC (langerin ؉ E-cadherin ؉ CD1a ؉ ) were generated in vitro and exposed to live L3. LC exposed to live L3 for 48 h showed no alterations in the cell surface markers CD14, CD86, CD83, CD207, E-cadherin, CD80, CD40, and HLA-DR or in mRNA expression of inflammation-associated genes, such as those for interleukin 18 (IL-18), IL-18BP, and caspase 1. In contrast to L3, live tachyzoites of Toxoplasma gondii, an intracellular parasite, induced production of CXCL9, IP-10, and IL-6 in LC. Furthermore, preexposure of LC to L3 did not alter Toll-like receptor 3 (TLR3)-or TLR4-mediated expression of the proinflammatory cytokines IL-1␤, gamma interferon (IFN-␥), IL-6, or IL-10. Interestingly, cocultures of KC and LC produced significantly more IL-18, IL-1␣, and IL-8 than did cultures of LC alone, although exposure of the cocultures to live L3 did not result in altered cytokine production. Microarray examination of ex vivo LC from skin blisters that were exposed to live L3 also showed few significant changes in gene expression compared with unexposed blisters, further underscoring the relatively muted response of LC to L3. Our data suggest that failure by LC to initiate an inflammatory response to the invasive stage of filarial parasites may be a strategy for immune evasion by the filarial parasite. L ymphatic filariasis (LF) caused by the parasitic nematodesWuchereria bancrofti, Brugia malayi, and Brugia timori infects approximately 120 million people worldwide in 72 countries. The disfiguring clinical manifestations, such as lymphedema and hydrocele, result in substantial morbidity and social stigma (1). Infection in LF is initiated when mosquito-derived third-stage larvae (L3) are deposited in the skin, an organ containing innate cells, primarily epidermal-resident Langerhans cells (LC) and keratinocytes (KC). Given the parasites' route through the skin, it is likely that the early interaction between L3 and innate cells in the skin-LC in particular-conditions the initiation of the L3-specific immune response, as LC are known to migrate to the draining lymph nodes (LN) soon after antigen internalization.LC are a subset of antigen-presenting dendritic cells (DC) that are located in the epidermal layer of the skin. LC become activated after antigen internalization and mature phenotypically and functionally (reviewed in references 2 and 3). Upon activation, adhesion molecules (such as E-cadherin) are downregulated to allow migration from the skin to the LN, where mature LC can activate naïve T cells and initiate T cell development (reviewed in references 2 and 3).Until recently, LC were considered the major antigen-presenting cells (APC) responsible f...

Attempts to Image the Early Inflammatory Response during Infection with the Lymphatic Filarial Nematode Brugia pahangi in a Mouse Model

“…The lack of specificity at later time points of infection could arise either because of the migration of developing larvae away from the site of infection or, alternatively, it could reflect the suppression of immune responses, a well-documented characteristic of lymphatic filarial nematodes [24,25,26]. Studies in the only fully permissive rodent host of Brugia species, the Mongolian jird, demonstrated that L3 rapidly migrated from the site of injection in the hind limb to the lymphatic system, with the majority of developing adults establishing in the lymphatics of the spermatic cord [27,28].…”

Human innate lymphoid cells (ILCs) in filarial infections

“…Whether L3 has a similar effect on skin resident ILC subsets remains unclear. However, these previous studies do demonstrate that L3 fails to induce ILC stimulating cytokines such as IL‐1β, IL‐18, IL‐12p40 or TSLP, alarmins IL‐25 and IL‐33 were not evaluated. The activation of cutaneous ILCs by LC is further hampered by the spatial disparity between ILCs (found predominately in the upper dermal layer) and LC (in the epidermal layer) in normal skin.…”

“…The response of skin resident cells such as Langerhans cells (LC), keratinocytes and dendritic cells (DC) to the invading L3 stage of B. malayi can be best described as quiescent demonstrating that filarial parasites can evade the immune response in the cutaneous tissue. Whether L3 has a similar effect on skin resident ILC subsets remains unclear.…”

Functional Impairment of Murine Dendritic Cell Subsets following Infection with Infective Larval Stage 3 of Brugia malayi

“…These include dampening of the host's proinflammatory cytokine response, attenuating the functions of innate immune cells; generating regulatory T cells; and impairing the activation, maturation, and functions of host dendritic cells (DCs), leading to their functional impairment (2)(3)(4)(5)(6)(7)(8)(9). Impairment of host Langerhans cells has also been reported during lymphatic filarial infections, which suggests that parasites not only interfere with the functions of Langerhans cells, but have also developed means to expertly evade antigen (Ag)-presenting cell (APC) detection in the host skin (1,10). We recently documented the role of lung eosinophils and functional impairment of lung macrophages during filarial manifestation of tropical pulmonary eosinophilia (TPE) (11).…”

“…arasites have evolved many diverse and novel strategies to evade the host immune response (1). These include dampening of the host's proinflammatory cytokine response, attenuating the functions of innate immune cells; generating regulatory T cells; and impairing the activation, maturation, and functions of host dendritic cells (DCs), leading to their functional impairment (2)(3)(4)(5)(6)(7)(8)(9).…”