Loa loa is a filarial parasite transmitted by tabanid female flies of the genus Chrysops (C silacea and C dimidiate). The incidence of infection within endemic region of the central and west African rain forest is high with 20-40% of the population being microfilaraemic , and about twice as many habouring adult worms without showing patent microfilaraemia (Dupont et al.,2007). The adult worms actively migrate through subcutaneous tissues at rates of up to 1cm/ min. Female Loa loa measures 50- 70mm in length and 0.5mm in diameter, while the males measures 30 -35mm in length and 0.4mm in diameter. The microfilariae forms, measures 290-300µm by 6-8µm in size. During infection the microfilariae forms are released into the blood stream, where they become numerous between 10a m and 2pm(diurnal periodicity).
Moreso, the presence of the sheath and three or more terminal nuclei distinguish the microfilariae of L. loa from other blood –borne microfilariae. ( Strickland, 2000) Transmission is by day –biting female tabanid flies, which pick up the microfilaria of L loa during blood meals . The injested microfilariae lose their sheath , penetrate the gut wall of the tabanid female fly, and migrate to the cells of the fat body , where they molt twice . The infective filariform larvae (L3)develop in 10 to 12 days and moves to the proboscis. When new host is biting by the female tabanid fly, the infective filariform larvae are injected and develop into adult worms over the course of 6- 12months .( John and Wayne, 2005) L loa infection ( Loiasis) is quite broad , ranging from asymptomatic infection to life threatening complication, which includes meningoencephalitis ,renal failure and endomyocardial fibrosis.
Thus , L loa infection often induces a mild to moderate pathology with patients presenting with pruritis, localized angioedema (Calabar swelling), arthralgia or ocular problems caused by conjunctival migration of adult worms. Also, fibrotic or inflammatory reactions around adult worm may cause hydrocele or intestinal blockage. (Strickland, 2000) The level of microfilariaemia is a critical parameter in the transmission of disease(Piessens and Partono ,2007). Immunity may be seen as a control measure of microfilariaemia, killing of adult worm or a resistance to infection that operates against the infective L3 stage. However, studies of the host immune response mechanisms implicated in the control of microfilaraemia , in the amicrofilaraemic ( Mf- ) individual have shown evidence of antibody- dependent cell cytotoxicity, not only for Loa loa infection, but also for other filariasis.
Thus, the circulating anti- sheath antibodies is present in sera of amicrofilaraemic (Mf- ) Loa loa infected individual and absent in heavily infected (Mf+)microfilaraemic individual ( Pinder et al ., 1990) Many studies on molecular biology, concerning cellular immune responses induced by filariae infections and their implication in protection and control of microfilaraemia have been carried out. Although , no studies have been published on the cellular response of Loa loa , but a greater cellular reactivity have been reported in non – endemic individual,who are amicrofilaraemic(Mf) , in comparison with endemic individual who are microfilaraemic (Mf+) infected with Loa loa(ref).
Thus , the T -cell cellular response plays an important role in mediating immunity and major role for antibody dependent cellular cytotoxic mechanisms in destroying parasites. (Couissinier and Dessein, 1995) The objective of this term paper aims at looking at the role of pathology , mediated by cellular immune response in an Loa loa infected individuals.
Source: (www.cdc.gov) Date :02/19/2011 Figure 1. Diagrammatic LIFE CYCLE OF Loa loa
During a blood meal, an infected fly (genus Chrysops, day-biting flies) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound. The larvae develop into adults that commonly reside in subcutaneous tissue. The female worms measure 50 to 70 mm in length and 0.5 mm in diameter, while the males measure 30 to 35 mm in length and 0.4 mm in diameter. Adults produce microfilariae measuring 250 to 300 μm by 6 to 8 μm, which are sheathed and have diurnal periodicity.
Microfilariae are usually recovered from spinal fluids, urine, and sputum. During the day they are found in peripheral blood, but during the non- circulation phase, they are found in the lungs. The tabanid fly ingests microfilariae during a blood meal. After ingestion, the microfilariae lose their sheaths and migrate from the fly’s midgut through the hemocoel to the thoracic muscles of the arthropod. There the microfilariae develop into first-stage larvae (L1) and subsequently into third-stage infective larvae (L3). The third-stage infective larvae migrate to the fly proboscis and can infect another human when the fly takes a blood meal.
PATHOLOGY of Loa loa Clinical manifestations are variable and are more significant in visitors to an endemic region than in indigenous people. Severity ranges from a mild nuisance as the occasional worm passes beneath the conjunctiva of the eye to significant CNS invasion and coma in people with a high microfilaremia. (Strickland, 2000) The most common and characteristic findings in loiasis are Calabar swellings, which are focal regions of angioedema, usually located in the extremities. These erythematous swellings occur suddenly, range in size from 5 to 15 cm, and resolve gradually over hours to days. The cause is unknown, but they may represent an immune response to antigenic material at a region where the worm has migrated. Calabar swellings generally occur at only one site at a time and may recur sporadically for years, even after a person has left an endemic region.
Interestingly, they are more common in visitors to an endemic region than in the local inhabitants. Fatigue and arthralgias also are not uncommon. ( Strickland ,2000) Subconjunctival migration of the adult worm, which is the eye worm, is generally accompanied by transient swelling of the eye lid and intense conjunctivitis. Although most episode resolve spontaneously and completely, however rare cases of retinal artery occlusion and macular retinopathy due to aberrant migration of the adult worm have reported (Ralph and Eagle(Jr), 2010). The most serious complication of Loa loa infection is meningoencephalitis, which is associated with the central nervous system CNS and occurs predominantly in patients with high numbers of circulating microfilariae. The severity of CNS involvement ranges from mild headache, meningismus coma and death. More so, the microfilariae are found in the cerebrospinal fluid, and in fatal cases, degenerating microfilariae result to necrotic granulomas in the brain. ( Oyerinde , 1999)
Another serious complication associated Loa loa infection, is membranous glomerulonephritis. It occurs in patients with hematuria and proteinuria, which may be due to immune complex. Also, Loiasis may be one cause of tropical pulmonary eosinophilia. Lymphadenopathy and lymphadenitis are also features of loiasis , but are less prevalent than in other filarial infection. Thus , when Loa loa microfilariae are found within lymph nodes , they may be intravascular or within adjacent microabscesses, they also wander throughout the body and have been reported seen in sleep , lung , gut and CNS.(Oyerinde , 1999) Loiasis have also been implicated in the etiology of some cases of endomyocardial fibrosis in equatorial Africa based on the higher prevalence of endomyocardial fibrosis in Loa – endemic areas than in other regions in Africa and higher level of antibodies detected in some individuals and also higher levels of antifilarial antibodies is reported to have been detected in some individual with endomyocardial fibrosis. (Oyerinde, 1999)
(Source. Marty and Anderson, 1995) Figure 2. Adult nematodes migrating beneath the conjunctiva of the human eye. .
IMMUNE RESPONSE AND MOLECULAR BIOLOGY OF Loa loa Immunity may be seen as control of microfilaraemia, killing of adult worm or a resistance to infection that operates against the infective L3 stage. Like the other microfilarial nematode , Loa loa is able to survive in it host by modulating the host immune response .However, studies of the host immune mechanism implicated in the control of microfilaraemia in the amicrofilaraemic individuals have shown evidence of antibody -dependent cellular cytotoxicity in Loa loa infection.( Baize et al.,1997 ). Circulating anti –sheath antibodies have been reported to be present in the sera of amicrofilaraemic (Mf-) individual and absent in the sera of microfilaraemic positive individual (Mf+).
This antibodies are effective in mediating complement-dependent leukocyte in adherence to micofilariae.( Baize et al., 1997) Many studies on molecular biology, concerning cellular immune responses induced by filariae infections and their implication in protection and control of microfilaraemia have been carried out. Although , no studies have been published on the cellular response of Loa loa , but a greater cellular reactivity have been reported in non – endemic individual,who are amicrofilaraemic(Mf-) , in comparison with endemic individual who are microfilaraemic (Mf+) infected with Loa loa. Thus , the T -cell cellular response plays an important role in mediating immunity and major role for antibody dependent cellular cytotoxic mechanisms in destroying parasites.( Maizels et al,2008).
Recently, attention is been paid to the involvement of T helper (Th) subset in antifilarial response. The T – cell response plays an important role in mediating immunity and a major role for antibody dependent cellular cytotoxic mechanisms in damaging parasites. Moreover , many studies have compared the proliferation and cytokine profile of peripheral blood mononuclear cells (PBMC) from microfilaraemic (MF+)individual and amicrofilaraemic individual(Mf -) infected with Loa loa in response to antigens of several parasitic stage. Thus , a stronger lymphoproliferative response and consistent levels of both Th1 ( IL-2 –interleukin- 2,IFN-γ – interferon gamma) and Th2 (IL -4,IL-5) type cytokine are reported to be observed in response to adult worm and microfilariae antigen in amicrofilaraemic (Mf-) patient, while the microfilariae positive(Mf+) patient is characterized by unresponsiveness of T cell to proliferation and production of cytokine .( Baize et al., 1997)
The unresponsiveness of T cell in microfilariae positive individual (Mf+) is reportedly associated with the IL-10 cytokines ,which down regulate the function of both the Th-1 and Th-2 cells by inhibiting the proliferation and production of IFN- γ, IL-4 and IL-5. Moreover, a significant high production of IL-10 by amicrofilaraemic (Mf-) individual, compared with microfilariae positive (MF+) individual and similar expression of IL-10 mRNA support the guess that IL-10 alone is not responsible for the unresponsiveness of the T cell in Mf+.( Karita et al.,2010) Furthermore ,the adult female worm and the infective larva L3 elicit Th2 responses , with high IL 4 production and appearance of IgG1 and IgE antibodies ,whereas exposure only to microfilariae elicits Th1 responses , characterized by high initial IFN-γ production and IgGa antibody. However, chronic exposure to microfilariae can lead to Th2 responses
The pathology of filariasis is immune- mediated, in which the host immune response plays a major role in protecting and controlling infection in individuals. Although , study carried out on the cellular immune response, concerning the proliferation and production T cellular response in both amicrofilaraemic (Mf-) and microfilariae ( Mf+) individual , is indicative of Th1 and Th2 cytokines response to adult worm and microfilariae antigen in amicrofilariae (Mf-) , and unresponsive in microfilariae (Mf+)(ref).However, T cell unresponsiveness in Mf+ patients associated with the IL-10 down regulation of the Th-1 and Th-2 cytokines is not a conclusive evidence of T cell unresponsiveness to microfilariae positive (Mf+) patient.
Baize ,S, Wahl, G, Soboslay,PT, Egwang,TG, and Georges,AJ, (1997). T helper responsiveness in human Loa loa infection; defective specific proliferation and cytokine production by CD4+ T cells fron micofilaraemic subjects compared with amicrofilaraemics. Clin Exp Immunol 108:272-278 .
Couissinier – Paris ,P, and Dessein ,AJ, (1995). Schistosomal –specific helper T cell clones from subjects resistant to infection by Schistosoma mansoni are Th0/2. European Journal Immunology 25:2295-302
Dupont , A, Zue-N’dong , J, and Pinder, M, (2007). Common occurrence of amicrofilaraemic Loaloa filariasis within the endemic
region. Trans R soc Trop. Med Hyg, 82:730 John, MG, and Wayne, M, (2005). Filarial infections , pp 6. Parasitic Infections of the Skin, 6th (ed) John Wiley and Sons, New York
Karita ,H, Taru ,M, and Sakari ,JT, (2010). Loa loa Microfilariae Evade Complement Attack In Vivo by Acquiring Regulatory Proteins from Host Plasma, pp 3886. In; Infection and Immunity , volume 77, America Society of Microbiology.
Maizels , RM, Bundy ,DAP, Selkirk, ME, Smith, DF, Anderson ,RM,( 2008). Immunological
modulation and evasion by helminthes parasites in human populations. Nature 365 :797-
Oyerinde, JPO, (1999). The filarial worm,pp 256-257. Essential of Tropical Medical Parasitology , 1st (ed) University of Lagos Press.
Piessens ,WF, and Partono , F, (2007). Host-vector –parasite relationships in human filariasis. Semin Infect Dis 3:131-5
Pinder , M, Dupont, A, Egwang ,TG, (1990) . Identification of a surface on Loaloa microfilariae the recognition of which correlates with the amicrofilaremic state in man .Journal Immunology 141:2480-6
Ralph , C, and Eagle(Jr), MD, (2010). Ocular Pathology Review . Director, Department Of Pathology,
Wills Eye Hospital
Strickland, GT, (2000). Filarial Infection , pp 754-755. Hunter’s Tropical Medicine and Emerging Infectious Diseases, 8th (ed).