PENINGKATAN RESPON IMUN ADAPTIF PADA ASOSIASI DENGAN INFEKSI LATEN Wuchereria bancrofti

Seminar 1 Agus Jaya/1106152413/guru

Pendahuluan
Di dunia terdapat 1,3 miliar penduduk yang berisiko tertular penyakit kaki gajah di lebih dari 83 negara dan 60% kasus berada di Asia Tenggara.1,10 filariasis di dunia menghabiskan dana 5 juta US$ setiap tahun untuk penanggulangannnya dan menduduki ranking 3 setelah malaria dan tuberculosis.3 WHO: The Global Goal of Elimination of Lymphatic Filariasis as a Public Health Problem by the Year 2020. Lebih dari 90% infeksi ini ditimbulkan oleh Wucheria bancrofti dan cacing dewasa berada dalam sistem limfatik melepaskan jutaan mikrofilaria (MF), yang secara periodik beredar dalam darah.4

FIGURE 109 Functions of TH2 cells. CD4+ T cells that differentiate into TH2 cells secrete IL-4, IL-5, and IL-13. IL-4 (and IL-13) act on B cells to stimulate production of antibodies that bind to mast cells, such as IgE. IL-4 is also an autocrine growth and differentiation cytokine for TH2 cells. IL-5 activates eosinophils, a response that is important for defense against helminthic infections. IL-4 and IL-13 are involved in barrier immunity, induce an alternative pathway of macrophage activation, and inhibit classical, TH1- mediated macrophage activation.

Respon imun adaptif terhadap cacing

Susceptible, resistance, and pathology

Hasil penelitian
(Kathrin Arndts, dkk. Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany)2008,Ghana

Responden: Pria(18-50 th) yg terinfeksi Wb asymptomatic n=159 97 MF+, 62 MF Pembanding 22 orang sehat tanpa infeksi EN (endemic Normal)

Figure 1. Active circulation of MF is associated with the number of worm nests.

Figure 1. Active circulation of MF is associated with the number of worm nests. Using ultrasound, infected individuals were examined for (A) the lymph dilation around the worm nests and (B) for the amount of worm nests (FDS). In addition, patients were also examined for (C) the maximum degree of their supratesticular lymph dilation, presented as a staging system. Box whisker plots in (A) show median, interquartile ranges and outliers of individually tested patients. Bars in (B) and (C) show the number of individuals and their correlating amount of worm nests or lymph dilation respectively. Data in (B) were tested for significance with the Cochran-Armitage trend test (p<0.001).

Figure 2. Patent infection alters filarial-specific Th2-like responses.

Arndts K, Deininger S, Specht S, Klarmann U, et al. (2012) Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti. PLoS Negl Trop Dis 6(4): e1611. doi:10.1371/journal.pntd.0001611 http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0001611

Figure 2. Patent infection alters filarial-specific Th2-like responses. Isolated PBMCs (2105/well) from endemic controls (EN) or filarialinfected MF+ or MF patients were stimulated with either anti-CD3/antiCD28 (10 g/ml/2.5 g/ml; A and E), Brugia malayi extract (B.m., 5 g/ml; B and F), MSP-1 0.25 g/ml; C and G) or LPS (50 ng/ml; D and H) for 72 hours. Thereafter, levels of IL-5 (AD) or IL-13 (EH) were measured in the culture supernatants via ELISA. Graphs show box whiskers with median, interquartile ranges and outliers after background subtraction. Statistical significances between the indicated groups were obtained after KruskalWallis and Mann-Whitney-U tests.

Figure 3. Latent infected patients show elevated IL-17 but not Th1-like responses.

Arndts K, Deininger S, Specht S, Klarmann U, et al. (2012) Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti. PLoS Negl Trop Dis 6(4): e1611. doi:10.1371/journal.pntd.0001611 http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0001611

Figure 3. Latent infected patients show elevated IL-17 but not Th1-like responses. Isolated PBMCs (2105/well) from endemic controls (EN) or MF+ or MF patients suffering from LF were stimulated with either anti-CD3/antiCD28 (10 g/ml/2.5 g/ml; A and E), Brugia malayi extract (B.m. 5 g/ml; B and F), MSP-1 (0.25 g/ml; C and G) or LPS (50 ng/ml; D and H) for 72 hours. Thereafter, levels of IFN- (AD) or IL-17 (EH) were measured in the culture supernatants via ELISA. Graphs show box whiskers with median, interquartile ranges and outliers after background subtraction. Statistical significances between the indicated groups were obtained after KruskalWallis and Mann-Whitney-U tests.

Figure 4. Regulatory responses are enhanced in latently infected individuals.

Arndts K, Deininger S, Specht S, Klarmann U, et al. (2012) Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti. PLoS Negl Trop Dis 6(4): e1611. doi:10.1371/journal.pntd.0001611 http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0001611

Figure 4. Regulatory responses are enhanced in latently infected individuals. Isolated PBMCs from endemic controls (EN) or patients infected with W. bancrofti were stimulated with anti-CD3/anti-CD28 (10 g/ml/2.5 g/ml; A, E), Brugia malayi extract (5 g/ml, B, F), MSP-1 (0.25 g/ml; C, G) or LPS (50 ng/ml, D, H) for 72 hours. Thereafter, culture supernatant was tested via ELISA for cytokine release of IL-10 and IL-6. Graphs show box whiskers with median, interquartile ranges and outliers after background subtraction. Statistical significances between the indicated groups were obtained after Kruskal-Wallis and Mann-Whitney-U tests.

Figure 5. Circulating microfilariae dampen release of TNF.

Figure 5. Circulating microfilariae dampen release of TNF. Isolated PBMCs from endemic controls (EN) or patients suffering from LF were stimulated with anti-CD3/anti-CD28 (10 g/ml/2.5 g/ml; A), Brugia malayi extract (5 g/ml; B), LPS (50 ng/ml; C) or with MSP-1 (0.25 g/ml; D) for 72 hours. Thereafter, culture supernatant was tested via ELISA for cytokine release of TNF. Graphs show box whiskers with median, interquartile ranges and outliers after background subtraction. Statistical significances between the indicated groups were obtained after Kruskal-Wallis and Mann-Whitney-U tests.

Figure 6. Patently infected individuals present elevated levels of total IgE.

Arndts K, Deininger S, Specht S, Klarmann U, et al. (2012) Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti. PLoS Negl Trop Dis 6(4): e1611. doi:10.1371/journal.pntd.0001611 http://www.plosntd.org/article/info:doi/10.1371/journal.pntd.0001611

Figure 6. Patently infected individuals present elevated levels of total IgE. Plasma from all three groups was analyzed for the production of total IgG1 (A), IgG2 (B), IgG3 (C), IgG4 (D) and IgE (E) with the Cytometric Bead Array. (F) shows the ratio of IgG4 and IgE. Graphs show box whiskers with median, interquartile ranges and outliers. Statistical significances between the indicated groups were obtained after Kruskal-Wallis and Mann-Whitney-U tests.

Figure 7. Patent infected patients produce more filarial-specific IgG4.

Figure 7. Patent infected patients produce more filarial-specific IgG4. Plasma from all participants was investigated for the presence of helminth-specific immunoglobulins by ELISA. Plates were coated overnight with 5 g/ml B.m. extract in PBS (pH = 9.6), incubated with patient and control plasma overnight and analyzed for specific IgG1-4 and IgE. Presented are the ratios of antigen-specific antibodies IgG4/IgE (A), IgG4/IgG1 (B), IgG4/IgG2 (C) and IgG4/IgG3 (D). Graphs show box whiskers with median, interquartile ranges and outliers. Statistical significances between the indicated groups were obtained after Kruskal-Wallis and Mann-Whitney-U tests.

Kesimpulan
Secara ringkas, setelah dibandingkan dengan individu MF+, pasien amikrofilaremia menunjukkan profil peningkatan TNF, IL-17, IL-10, IL-6 dan respon filarial-spesifik Th2-like. Ditemukan pula bahwa usia tidak berkorelasi dengan peningkatan produksi sitokin, tetapi status infeksilah yang menentukan profil kekebalan tubuh. Pola imunosupresif pada pasien MF + dilengkapi dengan rasio tinggi IgG4/IgE tertentu. Prevalensi IgG4 memberikan perlindungan untuk host dan parasite, karena menyediakan mekanisme untuk melawan- mengatur tinggi IgE dan dengan demikian menghindari immunopatologi yang berlebihan. Perbedaan antara kedua kelompok yang terinfeksi, yang tidak menderita patologi klinis, menunjukkan bahwa keberadaan mikrofilaria tampak relevan untuk menginduksi imunosupresi. Penemuan ini memberikan wawasan baru dalam individu amikrofilaremia asimptomatik, dimana sebelumnya pasien ini diabaikan. Respon kekebalan tinggi mereka dapat memberikan kunci pada eludasi alternative terapi pengobatan yang diharapkan dapat memblokir penularan/transmisi yang berakibat dapat membasmi/eradikasi infeksi/penyakit.4

DAFTAR PUSTAKA
1. Subdit Filariasis Kemenkes RI. Rencana Nasional Program Akselerasi Eliminasi Filariasis Di Indonesia 2010-2014.Jakarta:April 2010. 2. Alam A, Garna H. Buku Ajar Divisi Infeksi Dan Penyakit Tropis. Jakarta: Sagung Seto, 2012. 3. Jan H.F.(et.al) Strategic emphases for tropical diseases research: a TDR perspective. TRENDS in Parasitology Vol.18 No.10 October 2002. 4. Arndts K, Deininger S, Specht S, Klarmann U, Mand S, et al. (2012) Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti. PLoS Negl Trop Dis 6(4): e1611. doi:10.1371/journal.pntd.000161 5. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. Ed.6. Philadelphia: Saunders Elsevier, 2010. 6. Bratawijaya KG, Rengganis I. Imunologi Dasar. Edisi 10. Jakarta: Badan Penerbit FKUI, 2012. 7. Kresno SB. Imunologi: diagnosis dan prosedur laboratorium. Edisi 5. Jakarta: Badan Penerbit FKUI, 2010. 8. Sutanto I, Ismid IS, Syarifudin PK, Sungkar S. Buku ajar parasitology kedokteran. Edisi ke 4. Jakarta: Badan Penerbit FKUI, 2008. 9. Nutman TB, Kazura JW. Filariasis. Dalam Guerrant RL. et al. Tropical Infectious Diseases. (e-book) 10. WHO. Weekly epidemiological record: Global programme to eliminate lymphatic filariasis: progress report 2011, 14 september 2012, 87th year. No. 37, 2012, 87, 345356