Mycetoma Pathogenesis

Unlike the life-threatening systemic fungal infections, there is no clear immune defect or deficiency known which could explain why people develop mycetoma.

Serological studies with the M. mycetomatis specific antigens showed that, Translationally Controlled Tumour Protein, Fructose bisphosphaealdolase and pyruvate kinase antibodies were elevated in both mycetoma patients and endemic controls. However, only the patients developed mycetoma. This suggested that all people from the endemic area have contacted this fungus at some stage but only a small portion developed the disease.

Mahgoub and his colleagues in 1973 had studied the cell mediated immunity of a group of mycetoma patients by means of the tuberculin test, 2,4-dinitrochlorobenzene sensitization and lymphocyte proliferation induced by phytohaemagglutinin and found defective T cell mediated responses especially in severely infected patients and in those patients who did not respond well to treatment.

This finding was supported by animal studies, since mycetoma was more successfully induced in athymic mice than in immunocompetent mice. However, on the other hand, Bendl and his colleagues had studied 31 patients with mycetoma but no immune defects were detected in that cohort.

 

dna helix

 

Since it was observed in endemic areas, that mycetoma is seen more frequent in certain families, either an environmental or a genetic factor seems to be important in the development of mycetoma. Van de Sande and colleagues therefore addressed the genetic susceptibility towards mycetoma by determining differences in allele frequencies for several single nucleotide polymorphisms (SNPs) in patients and healthy endemic controls.Two of those genetic studies addressed the role of single nucleotide polymorphisms (SNPs) in genes involved in the function of the immune system. In the first study, the role of SNPs in genes neutrophil function was addressed. In that study, 11 SNPs in eight genes involved in neutrophil function were studied. Significant differences were found in genes encoding for interleukin 8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP4), nitric oxide synthase 2 (NOS2) and complement receptor 1. The genotypes more commonly found in mycetoma patients for CXCL8, its receptor CXCR2 and TSP4 all were associated with a higher CXCL8 production in other studies. Therefore, this finding was confirmed by the measurement of high levels of CXCL8 in serum of mycetoma patients. In contrast, the NOS2 genotype obtained from the patients was associated with a lower Nitric oxide production. This finding was also confirmed by lower nitrite and nitrate levels in mycetoma patients.

Mhmoud and colleagues determined the role of interleukin 10 (IL-10) and CC chemokine ligand 5 (CCL5) in the granuloma formation of mycetoma. Two SNPS in the promoter region of IL-10 and three SNPs in the promoter region of CCL5 were determined. Significant differences in allele distribution were demonstrated for one of the SNPs in the IL-10 promoter and two of the SNPs in the CCL5 promoter between mycetoma patients and healthy controls. Both IL-10 and CCL5 were found to be present in the mycetoma granuloma and also secreted in the serum of patients. Since both CCL5 and IL-10 play important roles in granuloma formation in general, it looks like the granuloma formation, itself also plays an important role in the pathology of mycetoma.

Based on the results of these three genetic association studies performed in mycetoma patients, it can be concluded that, there are indeed subtle genetic differences between the Sudanese people who develop mycetoma and the people who don’t. The exact role of these genetic differences should be further studied.

The role of sex hormone synthesis was studied because a clear male predominance was seen in mycetoma. In one study, 5 SNPs in 5 genes involved in sex hormone synthesis were studied. Significant differences in allele frequencies were found for catechol-O-methyltransferase (COMT) and cytochrome p450 subfamily 19 (CYP19). The genotypes more often obtained in mycetoma patients for COMT and CYP19 were previously described as influencing 17-estradiol production. Also in the male mycetoma patients, significantly elevated serum levels of 17-estradiol were found. In contrast, in these patients, also lowered levels of dehydroepiandrosteron (DHEA) were found. The differences in hormone levels noted between mycetoma patients and healthy controls did not directly affect the fungus itself. Indirect effects on the patients' hormone regulated immune states are the more likely explanations for mycetoma susceptibility.

As described above, SNPs in genes involved in the pathology of mycetoma can contribute to the risk of developing mycetoma once the causative agent is introduced into the subcutaneous tissue, but next to that it can also contribute to the extent of the disease. In the above mentioned studies it was noted that two of the SNPs found to be associated with the size of the mycetoma lesion, namely NOS2 and COMT.

Mycetoma Pathogenesis

Unlike the life-threatening systemic fungal infections, there is no clear immune defect or deficiency known which could explain why people develop mycetoma.

Serological studies with the M. mycetomatis specific antigens showed that, Translationally Controlled Tumour Protein, Fructose bisphosphaealdolase and pyruvate kinase antibodies were elevated in both mycetoma patients and endemic controls. However, only the patients developed mycetoma. This suggested that all people from the endemic area have contacted this fungus at some stage but only a small portion developed the disease.

Mahgoub and his colleagues in 1973 had studied the cell mediated immunity of a group of mycetoma patients by means of the tuberculin test, 2,4-dinitrochlorobenzene sensitization and lymphocyte proliferation induced by phytohaemagglutinin and found defective T cell mediated responses especially in severely infected patients and in those patients who did not respond well to treatment.

This finding was supported by animal studies, since mycetoma was more successfully induced in athymic mice than in immunocompetent mice. However, on the other hand, Bendl and his colleagues had studied 31 patients with mycetoma but no immune defects were detected in that cohort.

 

dna helix

 

Since it was observed in endemic areas, that mycetoma is seen more frequent in certain families, either an environmental or a genetic factor seems to be important in the development of mycetoma. Van de Sande and colleagues therefore addressed the genetic susceptibility towards mycetoma by determining differences in allele frequencies for several single nucleotide polymorphisms (SNPs) in patients and healthy endemic controls.Two of those genetic studies addressed the role of single nucleotide polymorphisms (SNPs) in genes involved in the function of the immune system. In the first study, the role of SNPs in genes neutrophil function was addressed. In that study, 11 SNPs in eight genes involved in neutrophil function were studied. Significant differences were found in genes encoding for interleukin 8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP4), nitric oxide synthase 2 (NOS2) and complement receptor 1. The genotypes more commonly found in mycetoma patients for CXCL8, its receptor CXCR2 and TSP4 all were associated with a higher CXCL8 production in other studies. Therefore, this finding was confirmed by the measurement of high levels of CXCL8 in serum of mycetoma patients. In contrast, the NOS2 genotype obtained from the patients was associated with a lower Nitric oxide production. This finding was also confirmed by lower nitrite and nitrate levels in mycetoma patients.

Mhmoud and colleagues determined the role of interleukin 10 (IL-10) and CC chemokine ligand 5 (CCL5) in the granuloma formation of mycetoma. Two SNPS in the promoter region of IL-10 and three SNPs in the promoter region of CCL5 were determined. Significant differences in allele distribution were demonstrated for one of the SNPs in the IL-10 promoter and two of the SNPs in the CCL5 promoter between mycetoma patients and healthy controls. Both IL-10 and CCL5 were found to be present in the mycetoma granuloma and also secreted in the serum of patients. Since both CCL5 and IL-10 play important roles in granuloma formation in general, it looks like the granuloma formation, itself also plays an important role in the pathology of mycetoma.

Based on the results of these three genetic association studies performed in mycetoma patients, it can be concluded that, there are indeed subtle genetic differences between the Sudanese people who develop mycetoma and the people who don’t. The exact role of these genetic differences should be further studied.

The role of sex hormone synthesis was studied because a clear male predominance was seen in mycetoma. In one study, 5 SNPs in 5 genes involved in sex hormone synthesis were studied. Significant differences in allele frequencies were found for catechol-O-methyltransferase (COMT) and cytochrome p450 subfamily 19 (CYP19). The genotypes more often obtained in mycetoma patients for COMT and CYP19 were previously described as influencing 17-estradiol production. Also in the male mycetoma patients, significantly elevated serum levels of 17-estradiol were found. In contrast, in these patients, also lowered levels of dehydroepiandrosteron (DHEA) were found. The differences in hormone levels noted between mycetoma patients and healthy controls did not directly affect the fungus itself. Indirect effects on the patients' hormone regulated immune states are the more likely explanations for mycetoma susceptibility.

As described above, SNPs in genes involved in the pathology of mycetoma can contribute to the risk of developing mycetoma once the causative agent is introduced into the subcutaneous tissue, but next to that it can also contribute to the extent of the disease. In the above mentioned studies it was noted that two of the SNPs found to be associated with the size of the mycetoma lesion, namely NOS2 and COMT.

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