Abstract
BackgroundAlthough the etiology of Type 1 Diabetes mellitus (T1DM) has not been determined, genetic polymorphism in key genes, including SLC11A1, and association with Mycobacterium avium subspecies paratuberculosis (MAP) have been reported. We hypothesize that molecular mimicry between MAP Heat shock protein 65 K (Hsp65) and human Glutamic Acid Decarboxylase 65 K (GAD65) may be the trigger leading to autoimmune destruction of beta cells in patients exposed to MAP.MethodPeptide sequences of MAP Hsp65 and human GAD65 were investigated for amino acid sequence homology and cross reactivity. A total of 18 blood samples from T1DM and controls were evaluated for the presence of MAP.ResultsPeptide BLAST analysis revealed a 44% overall identity between MAP Hsp65 and GAD65 with 75% positives in a 16 amino acid region. PyMOL 3D-structural analyses identified the same 16 amino acid region as a potential epitope for antibody binding. Preliminary data suggests a cross reactivity between MAP Hsp65, and a healthy rat pancreatic tissue homogenate against plasma from T1DM patients and rabbit polyclonal anti-MAP IgG. Long-term culture of human blood resulted MAP detection in 3/10 T1DM and 4/8 controls whereas MAP IgG was detected in 5/10 T1DM samples and 3/8 non-diabetic controls.ConclusionThe high degree of homology between GAD65 and MAP Hsp65 in an antigenic peptide region supports a possible mycobacterial role in triggering autoimmune destruction of pancreatic cells in T1DM. Reactivity of T1DM patient sera with MAP Hsp65 supports this finding. Culture of MAP from the blood of T1DM patients is intriguing. Overall, the preliminary data are mixed and do not exclude a possible role for MAP in T1DM pathogenesis. A larger study including well-characterized controls is needed to investigate the intriguing question of whether MAP is associated with T1DM or not?
Highlights
The etiology of Type 1 Diabetes mellitus (T1DM) has not been determined, genetic polymorphism in key genes, including SLC11A1, and association with Mycobacterium avium subspecies paratuberculosis (MAP) have been reported
Long-term culture of human blood resulted MAP detection in 3/10 T1DM and 4/8 controls whereas MAP IgG was detected in 5/10 T1DM samples and 3/8 non-diabetic controls
A larger study including well-characterized controls is needed to investigate the intriguing question of whether MAP is associated with T1DM or not?
Summary
Bioinformatics analysis BProtein BLAST analysis was initialized to determine the sequence homology between peptide sequences of MAPHsp and human GAD 65 (http://blast.ncbi.nlm.nih.gov/Blast.cgi). Protein BLAST analysis was initialized to determine the sequence homology between peptide sequences of MAP. The peptide sequences of the proteins for the analysis were retrieved from Uniprot protein database (http://www.uniprot.org/). PyMOL analysis were retrieved from the protein data bank (http://www.rcsb.org/pdb/home/home.do) and were used to localize the homologous sequences of the proteins in their 3D conformation. Suggested to be a potential antigenic binding site leading to auto destruction of pancreatic beta cells [22]. Since the PyMOL 3D structure of MAP Hsp is not available, the available peptide sequence of the closely related Mtb Hsp was used. The anti-MAP Hsp antibodies may bind to the GAD65 epitope on the surface of Beta cell leading to their destruction.
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