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Immuneresponse to Mycetoma

Immuneresponse to Mycetoma. By/ Walaa Abdallah Omer November 2009. Introduction What is Mycetoma?

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Immuneresponse to Mycetoma

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  1. Immuneresponse to Mycetoma By/ Walaa Abdallah Omer November 2009.

  2. Introduction What is Mycetoma? Mycetoma is achronic granulomatous disease of humans andanimals characterized by draining sinuses that secrete grains of the causative organism. Mycotic mycetoma - usually more common in men (3:1 to 5:1) than in women. The disease results from the traumatic implantation of the aetiologic agent and usually involves the cutaneous and subcutaneous tissue, fascia and bone of the foot or hand. The legs and feet were commonly the sites of the infection, but all other body sites can be infected. Sinuses discharge serosanguinous fluid containing the granules which vary in size, colour and degree of hardness, depending on the aetiologic species, and are the hallmark of mycetoma.

  3. Types: According to the etiological agent, mycetoma can be divided to 2types: The common etiological agent in Sudan and neighboring countries is Madurella mycetomatis which causes the majority of the cases with the black grains.

  4. Geographical distribution: Mycetoma is a worldwide disease frequently occurs in the tropics with the highest prevalence being in Africa, most common in bare-footed populations living in tropical or subtropical regions. It is called Madura foot because the first case was found in Madura area in India.

  5. Pathogenicity: The infection follows inoculation of organisms, frequently through thorn punctures, wood splinters, or preexisting abrasions or trauma. After inoculation, these organisms grow and survive through the production of grains (also called granules or sclerotia), structures composed of masses of mycelial fungi or bacterial filaments and a matrix component. The matrix material has been shown to be host-derived with some pathogens. In eumycetoma, hyphal elements often have thickened cell walls toward the periphery of grains, potentially conferring protection against the host immune system

  6. Granuloma starts out as tumor-like to subcutaneous swelling. Progression to draining sinus tracts can take weeks, months, and even years, occurring more rapidly in actinomycetoma. It ruptures near the surface; infects deeper tissues including subcutaneous tissues and ligaments (tendons, muscles and bone are usually spared) small particles or grains leak out of the lesions. Location of lesions is mainly linked to exposure. The lesions are painless and slowly progressive; however, secondary bacterial infection or bone expansion may cause pain. (Margarita Asenjo. 2008)

  7. Immuneresponse:

  8. Cellular components: Mycetoma patients were investigated for cell-mediate immunity. Results seem to point towards deficiency in cell-mediated immunity at least partial if not whole. (1977,Mahgoub ES, Gumaa SA, El Hassan AM). Innate immunity cells: Grains are seen in histopathology within abscesses containing polymorphonuclear cells. Complement-dependent chemotaxis of polymorphonuclear leukocytes has been shown to be induced by both fungal and actinomycotic antigens in vitro. Cells of the innate immune system attempt to engulf and inactivate these organisms, but in disease ultimately fail to accomplish this goal. Abscesses containing grains are seen in association with granulomatous inflammation and fibrosis.

  9. Three types of immune responses have been described in response to the grains of mycetoma/ -Type I response is seen as neutrophils degranulate and adhere to the grain surface, leading to gradual disintegration of the grain. (stained positively for CD15) -Type II response is characterized by the disappearance of neutrophils and arrival of macrophages to clear grains and neutrophil debris. (CD68 (macrophages) and CD3 (T lymphocytes). - Type III response is marked by the formation of epithelioid granuloma. This host response does not appear to be able to control infection, but likely accounts for the partial spontaneous healing that is seen in the disease. (CD20 (B lymphocytes).

  10. As well as morphologically altered, displaying irregular and short dendritic processes, LC (Langerhans cells) were depleted both in ACM and EUM lesions when compared with normal skin. Results suggest that cellular mediated immunity may play a role in mycetoma pathogenesis. The morphological alterations and marked reduction of LC in mycetoma lesions might reflect a depressed cellular immune response, partially explaining the chronic course and unresponsiveness to treatment of this group of diseases. (Guimarães CC, Castro LG, Sotto MN. 2003)

  11. Tcells: Cell elements in the inflammatory infiltrate of skin lesions of actinomycetoma (ACM) and eumycetoma (EUM) were demonstrated, quantified and compared. Tissue response in both groups of mycetoma showed CD4+ and CD8+ T lymphocytes surrounding the neutrophils aggregates with macrophages, revealed by CD68 antibody, among them. ACM lesions showed a higher number of CD8+ lymphocytes and macrophages when compared with EUM lesions.

  12. Cytokines • The circulating levels of IFN-gamma increased more than 10 times the basal levelsand thelevels of IL-4, IL-6 and IL-10 also increased during the first 4 days of infection. (Salinas-Carmona MC, Torres-Lopez E, Ramos AI, 1999). • The cytokine profile in the lesion and regional lymph nodes was of adominant Th2 pattern (interleukins-10 and 4). (El Hassan AM, Fahal AH, Ahmed AO. 2001) • Activation of cellular immunity and production of cytokines are involved in resistance and elimination of the N. brasiliensis bacterial cells.

  13. The in situ production of cytokines in the microabscesses has been reported in the murine infection. TNF-alpha is produced in the first days of infection, decreasing later to non detectable quantities at day 90. IL–1beta, IFN gamma, TGF-beta, IL-10, IL-4, and IL-6 are produced constantly during the 90 days, but IL-6 is the only one with a significant increase once the mycetoma is fully established (90 d) ( Lucio Vera-Cabrera Mexico. 2009)

  14. Humoral immunity (Abs): Levels of immunoglobulins, IgG, IgM and IgA were determined. There was a definite rise in the IgM and IgA class of immunoglobulins and a decrease in IgG. Levels of antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in 13 patients with eumycetomas due to Madurella mycetomatis infections. Raised levels of specific IgM were observed in 12 patients, compared with normal human controls. By contrast, low levels of specific IgG were detected in some patients. Specific responses to separated protein antigens were investigated by immunoblotting.(1988, D.B. Wethered, M.A. Markey, R.J. Hay, E.S. Mahgoub, S.A. Gumaa) Anti-P24 immunoglobulin M (IgM) isotype antibodies were present as early as 7 days, IgG peaking 45 days after infection.

  15. The host immune response in humans and mice involves the production of high levels of anti– N. brasiliensis IgG antibodies and quantitation of these antibodies is important for diagnosis.(2009) IgM anti– N. brasiliensis antibodies can protect mice from an experimental infection.

  16. Predisposition to Mycetoma: • It is not clear whether persons who develop mycetoma have predisposing • immune deficits. Disease does not appear to be more common in immunocompromised hosts, and early studies of immune function in persons with mycetoma have not clearly documented a common deficit. (Bendl BJ, Mackey D, Al-Saati F, et al.1987).( Mahgoub ES, Gumaa SA, El Hassan AM. Immunological status of mycetoma patients. Bull Soc Pathol Exot Filiales. 1977) • It has been suggested that the greater frequency of disease in men is not completely explained by increased frequency of exposure to soil and plant material. Progesterone has been shown in vitro to inhibit the growth of • M. mycetomatis, P. romeroi, and N. brasiliensis. (Hernández F, López-Martínez R, Méndez-Tovar LJ, • et al.. 1995)

  17. At the molecular level: the first evidence of human genetic predisposition toward susceptibility to mycetoma was presented recently in 2007, 11 single nucleotide polymorphisms(SNPs) involved in neutrophil function were studied in a population of Sudanese mycetoma patients vs geographically and ethnically matched controls. Significant differences in allele distribution for IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP-4), NO synthase 2 (NOS2), and complement receptor 1 (CR1) were found. Further, the NOS2 polymorphism was clearly associated with lesion size. (van de Sande WWJ, Fahal A, Verbrugh H, et al. Polymorphisms in genes involved in innate immunity predispose toward mycetoma susceptibility. J Immunol. 2007)

  18. Diagnosis:

  19. Treatment: Treatment of this disease has proven to be difficult, and typically includes antimicrobial agents, surgery and amputation. Chemotherapy varies for actinomycetoma and eumycetoma. Treatment regimens are currently based on expert opinion because no randomized controlled trials have been performed. For eumycetoma: most commonly includes the use of azole antifungals. Itraconazole or ketoconazole are considered first-line azole agents in the treatment of this disease. For Actinomycetoma: streptomycin plus either trimethoprim-sulfamethoxazole (TMP-SMX) or dapsone. Gentamicin plus TMP-SMX. Streptomycin with either sulfadoxine-pyrimethamine or rifampin. A combination of penicillin, gentamicin, and TMP-SMX followed by TMP-SMX and amoxicillin. Duration of therapy is also not defined, and most patients receive 3 to 24 months of therapy to obtain an adequate response.

  20. Recommendations: More studies should be done to understand the pathogenicity and the body immune response to Mycetoma in order to have effective treatment and to get rid of this disease.

  21. Thank you Thank you

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