adjuvant-activity-mycobacterium-paratuberculosis-enhancing

Adjuvant Activity of <em>Mycobacterium paratuberculosis</em> in Enhancing the Immunogenicity of Autoantigens During Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) requires immunization by a MOG peptide emulsified in ...

Juntendo University

To better understand the mechanisms involved in the dynamics of Johne's disease in dairy cattle, this paper illustrates a novel way to link a within-host model for Mycobacterium avium ssp. paratuberculosis with an epidemiological model. The underlying variable in the within-host model is the time since infection. Two compartments, infected macrophages and T cells, of the within-host model feed into the epidemiological model through the direct transmission rate, disease-induced mortality rate, the vertical transmission rate, and the shedding of MAP into the environment. The epidemiological reproduction number depends on the within-host bacteria load in a complex way, exhibiting multiple peaks. A possible mechanism to account for the switch in shedding patterns of the bacteria in this disease is included in the within-host model, and its effect can be seen in the epidemiological reproduction model.

An immuno-epidemiological model for Johne's disease in cattle.

Several works have demonstrated the existence of a link between Mycobacterium avium subsp. paratuberculosis (MAP) and MS in Italy. In this study, we analyzed the serology of MAP in a Japanese population while looking at several markers of MAP. Fifty MS patients, 12 clinically isolated syndrome (CIS) patients, 30 other neurological disorders (OND) patients, and 50 healthy controls (HCs) were tested using ELISA for the presence of IgG antibodies toward immunodominant epitopes MAP_0106c121-132, homologues MBP85-98, homologues IRF5424-432, MAP_402718-32, and MAP_2694295-303. MAP-positive patients were also analyzed in relation to their clinical/demographic characteristics. Amongst all peptides, only antibodies against MAP_2694295-303 were more prevalent in MS patients (30%), as compared to OND patients (3%) (p = 0.009; area under roc curve (AUC) = 0.61) and HCs (2%) (p = 0.0004; AUC = 0.65) and in CIS patients (25%) compared to HCs (p = 0.023; AUC = 0.55). Logistic regression analysis showed a higher frequency of anti-MAP_2694295-303 antibodies in the sera of oligoclonal bands positive MS patients (p = 0.2; OR = 2, 95%CI: 0.55-7.7). These findings support the view that MAP could act as a risk factor or a triggering agent of MS in some Japanese patients with a genetic susceptibility to the mycobacterium.

Humoral response against host-mimetic homologous epitopes of Mycobacterium avium subsp. paratuberculosis in Japanese multiple sclerosis patients.

Mycobacterium avium subsp. paratuberculosis (MAP) and Mycobacterium bovis (BCG) have been associated to several human autoimmune diseases such as multiple sclerosis (MS), but there are conflicting evidence on the issue. The objective of this study is to evaluate their role in Japanese patients affected by inflammatory demyelinating disorders of the central nervous system (IDDs). A total of 97 IDDs subjects including 51 MS and 46 neuromyelitis optica spectrum disorder (NMOSD) patients, and 34 healthy controls (HCs) were tested for the detection of IgG, IgM and IgA against mycobacterial antigens by indirect ELISA. The levels of anti-MAP IgG were higher in MS patients compared to NMOSD patients (AUC = 0.59, p = 0.02) and HCs (AUC = 0.67, p = 0.01), and the anti-MAP antibodies were more prevalent in MS patients treated with interferon-beta (OR = 11.9; p = 0.004). Anti-BCG IgG antibodies were detected in 8% of MS, 32% of NMOSD and 18% of HCs, the difference between MS and NMOSD groups was statistically significant (AUC = 0.66, p = 0.005). Competition experiments showed that nonspecific IgM were elicited by common mycobacterial antigens. Our study provided further evidence for a possible association between MAP and MS, while BCG vaccination seemed to be inversely related to the risk of developing MS.

Altered humoral immunity to mycobacterial antigens in Japanese patients affected by inflammatory demyelinating diseases of the central nervous system.

Levels of Japanese cedar pollen () have increased in Japan and cedar pollinosis caused by Japanese cedar pollen has been reported in dogs. Serum levels of immunoglobulin E (IgE) against Cry j 1 and Cry j 2 in dogs raised in institutes and treated at veterinary hospitals in Japan were thus investigated. A total of 71 sera obtained from two institutes and 87 sera obtained from veterinary hospitals in the Hyogo and Kanagawa Prefectures were analyzed in this study. Serum levels of IgE were measured using the enzyme-linked immunosorbent assay with commercial purified Cry j 1 and Cry j 2. IgE against Cry j 1 and Cry j 2 in sera obtained from the two institutes were detected, despite the dogs being bred in enclosed areas. Moreover, significant differences were noted in the serum levels of IgE against Cry j 1 and Cry j 2 between the two institutes. The number of samples showing Cry j 1 or Cry j 2 levels above the cut-off values was greater in the Kanagawa Prefecture than in the Hyogo Prefecture. In total, 14 dogs showed Cry j 1 and Cry j 2 levels greater than the cut-off values in the Hyogo Prefecture, and only three such dogs were seen in the Kanagawa Prefecture. A significant correlation between serum levels against both allergens was observed (r² = 0.6931,  < 0.0001).

Seroprevalence of Immunoglobulin E Antibodies against Japanese Cedar Pollen Allergens Cry j 1 and Cry j 2 in Dogs Bred in Japan.

Due to an error during production, the column title of  and  are misaligned in the Results section of the published paper [...].

Erratum: Kuribayashi, T. et al. Seroprevalence of Immunoglobulin E Antibodies against Japanese Cedar Pollen Allergens Cry j1 and Cry j2 in Dogs Bred in Japan.  2018, , 79.

Local synthesis of antibodies and presence of oligoclonal bands in the cerebrospinal fluid (CSF) are hallmarks of multiple sclerosis (MS). We investigated the frequency of antibodies against mycobacterial and relevant human epitopes in the CSF of patients with MS or neuromyelitis optica spectrum disorder (NMOSD) and whether these antibodies differed from those present in the serum. Matched serum and CSF samples from 46 patients with MS, 42 patients with NMOSD, and 29 age-matched and sex-matched control subjects were screened retrospectively for the presence of antibodies against  subsp.  (MAP) pentapeptide (MAP_5p), MAP_2694, and myelin basic protein (MBP) peptides by using indirect ELISA. Serum levels of anti-MAP_5p and anti-MAP_2694 antibodies were highly prevalent in patients with MS when compared to patients with NMOSD and controls. Several patients with MS had detectable anti-MAP_5p and anti-MAP_2694 antibodies in the CSF. Furthermore, a group of patients with MS showed intrathecally restricted production of antibodies against these peptides. Women appeared to mount a stronger humoral response to mycobacterial peptides than men. No significant difference in the frequency of anti-MBP antibodies was found between patients with MS and those with NMOSD. These data highlight the zoonotic potential of MAP, which suggests its involvement in MS etiopathogenesis.

Anti-Mycobacterial Antibodies in Paired Cerebrospinal Fluid and Serum Samples from Japanese Patients with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder.

Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne's disease in ruminants, has been linked as a possible risk factor for human multiple sclerosis. In the current study we investigated the adjuvant effect of MAP on experimental autoimmune encephalomyelitis (EAE). Groups of C57BL/6 mice were actively immunized with myelin oligodendrocyte glycoprotein (MOG)  peptide emulsified in incomplete Freund's adjuvant modified containing heat-killed MAP (MIFA). MOG-MIFA immunized mice showed an early disease onset and more severe clinical scores in comparison with MOG-CFA immunized mice, demonstrating for the first time the adjuvant effect of MAP on EAE development.

Adjuvant and antigenic properties of Mycobacterium avium subsp. paratuberculosis on experimental autoimmune encephalomyelitis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Altered humoral immunity to mycobacterial antigens in Japanese patients affected by inflammatory demyelinating diseases of the central nervous system.

In this study, the seroprevalence of immunoglobulin G (IgG) antibodies against  subsp.  (MAP) in dogs bred in Japan was evaluated. Ninety-two non-clinical samples were obtained from three institutes and fifty-seven clinical samples were obtained from a veterinary hospital in Japan. Serum titers of total IgG, IgG and IgG isotype antibodies against MAP were measured using an indirect enzyme-linked immunosorbent assay (ELISA). The IgG antibodies against MAP in non-clinical serum obtained from three institutes was observed to be 2.4%, 20% and 9.0%. Similarly, the IgG antibodies titers against MAP were observed to be 7%, 20% and 0%. Lastly, the IgG antibodies against MAP were observed to be 7%, 20% and 4.4%. No significance differences in these titers were observed among the three institutes. The IgG, IgG and IgG antibodies in serum obtained from a veterinary hospital were observed to be 55.3%, 42% and 42%, respectively. Significant differences were found between the non-clinical and clinical samples. The titers in the clinical samples showed a high degree of variance, whereas low variance was found in the non-clinical samples. The IgG antibody levels were thought to be induced following exposure to MAP-contaminated feed. The difference in titers between the clinical and non-clinical samples is likely to be related to the amount of MAP antigen contamination in dog foods.

Seroprevalence of Immunoglobulin G Antibodies Against  subsp.  in Dogs Bred in Japan.

Findings in humans and animals have demonstrated a potential role for Mycobacterium avium subsp. paratuberculosis (MAP) antigenic components in encephalitogenic T cell activation. Here we reported that oral administration of MAP activates the mucosal immunity and exacerbates active experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice, modulating the immune cell traffic from secondary lymphoid organs to central nervous system. The detection of antigenic mycobacterial components by intestinal antigen-presenting cells may modulate the immune system and the subsequent inflammatory status through various signaling mechanisms, including the synthesis of pro-inflammatory cytokines involved in EAE pathogenesis.

Article	Year
An immuno-epidemiological model for Johne's disease in cattle. Veterinary research\| PubMed ID: 26091672	2015
Humoral response against host-mimetic homologous epitopes of Mycobacterium avium subsp. paratuberculosis in Japanese multiple sclerosis patients. Scientific reports\| PubMed ID: 27356622	2016
Altered humoral immunity to mycobacterial antigens in Japanese patients affected by inflammatory demyelinating diseases of the central nervous system. Scientific reports\| PubMed ID: 28600575	2017
Seroprevalence of Immunoglobulin E Antibodies against Japanese Cedar Pollen Allergens Cry j 1 and Cry j 2 in Dogs Bred in Japan. Veterinary sciences\| PubMed ID: 30208581	2018
Erratum: Kuribayashi, T. et al. Seroprevalence of Immunoglobulin E Antibodies against Japanese Cedar Pollen Allergens Cry j1 and Cry j2 in Dogs Bred in Japan. 2018, , 79. Veterinary sciences\| PubMed ID: 30513569	2018
Anti-Mycobacterial Antibodies in Paired Cerebrospinal Fluid and Serum Samples from Japanese Patients with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder. Journal of clinical medicine\| PubMed ID: 30544526	2018
Adjuvant and antigenic properties of Mycobacterium avium subsp. paratuberculosis on experimental autoimmune encephalomyelitis. Journal of neuroimmunology\| PubMed ID: 30738572	2019
Author Correction: Altered humoral immunity to mycobacterial antigens in Japanese patients affected by inflammatory demyelinating diseases of the central nervous system. Scientific reports\| PubMed ID: 32042055	2020
Seroprevalence of Immunoglobulin G Antibodies Against subsp. in Dogs Bred in Japan. Veterinary sciences\| PubMed ID: 32709114	2020
A mucosal immune response induced by oral administration of heat-killed Mycobacterium avium subsp. paratuberculosis exacerbates EAE. Journal of neuroimmunology\| PubMed ID: 33454553	2021

Eiichi Momotani

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