UVM Theses and Dissertations
Format:
Print
Author:
Saligrama, Naresha
Dept./Program:
Cell and Molecular Biology Program
Year:
2013
Degree:
Ph. D.
Abstract:
Add Abstract here; divide long abstracts with more than one paragraph into multiple 520 fields.
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system affecting mainly young adults. MS is a complex disease thought to be mediated by an intricate interaction between a susceptible genome and environmental factors. Multiple interacting risk loci have been identified by genome-wide association studies.
Experimental allergic encephalomyelitis (EAE), the principal animal model for MS, has been used extensively to investigate the genetic factors underlying the immunopathogenesis of MS. EAE, like MS, is polygenic in nature and our lab, and others, have identified many of these quantitative trait loci and disease associated genes. One such locus is Bordetella pertussis induced histamine sensitization (Bphs) controlling susceptibility to histamine-induced pertussis toxin (PTX) sensitization, EAE, and experimental allergic orchitis. Later, histamine receptor H₁ (Hrh1) was identified to be the gene underlying Bphs.
Histamine (HA) (2-[4-imodazole]-ethylamine) is a ubiquitously distributed biogenic monomine that regulates many physiological and pathological functions. HA exerts its effects through binding to four 7-transmembrane G-protein coupled (GPC) histamine receptors (HR), H₁R, H₂R, H₃R, and H₄R. The role of HA in the immunopathogenesis of MS and EAE has been well documented.
H₁R and H₂R are expressed by immune cells and mice deficient for either H₁R (H₁RKO) or H₂R (H₂RKO) exhibit reduced EAE severity compared to wild-type (WT) mice. We have investigated the role of H₁R in EAE susceptibility by re-expressing H₁R in H₁RKO T cells, endothelial cells, and antigen presenting cells (APCs). Our results suggest that the re-expression of H₁R in T cells regulates encephalitogenic responses and its re-expression in endothelial cells protects H₁RKO mice from EAE.
In addition, as discussed in Chapter 3, the re-expression of H₁R in APCs does not contribute to EAE susceptibility or affect encephalitogenic T cell responses. Our results highlight the cell specific effects of H₁R in EAE susceptibility. Furthermore, we have explored the role of H₂R in EAE susceptibility by re-expressing this receptor in H₂RKO T cells and have shown in Chapter 5 that H₂R signaling directly in T cells contributes to EAE susceptibility when induced in the presence of PTX.
Whereas H₁R and H₂R are propathogenic, H₃R and H₄R are antipathogenic in EAE. Therefore, in Chapter 2, we investigated the combinatorial effects of each class of HR on EAE susceptibility by generating double KO mice (H₁H₂RKO vs. H₃H₄RKO). Importantly, our results suggest that the combinational targeting of HRs may be an appropriate disease modifying therapy in MS. In addition, our results suggest there is compensation among HRs, such that in the absence of one or more HRs there is compensatory upregulation of the remaining HRs.
Historically, HA is known to signal through four known GPC-HRs. However, there is evidence for HA signaling through non-GPCRs, like the [upsilon]-aminobutyric acid receptor (GABAaR). In Chapter 4, we show that mice deficient for the four known HRs (H₁₄RKO) exhibit increased resistance to EAE compared to WT mice and histidine decarboxylase deficient mice (HDCKO), which lack systemic HA. Therefore, in light of the opposing results from the HDCKO studies, our data suggest that HA may initiate signaling independently of H₁₋₄R and supports the existence of an alternative HAergic pathway in regulating EAE.
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system affecting mainly young adults. MS is a complex disease thought to be mediated by an intricate interaction between a susceptible genome and environmental factors. Multiple interacting risk loci have been identified by genome-wide association studies.
Experimental allergic encephalomyelitis (EAE), the principal animal model for MS, has been used extensively to investigate the genetic factors underlying the immunopathogenesis of MS. EAE, like MS, is polygenic in nature and our lab, and others, have identified many of these quantitative trait loci and disease associated genes. One such locus is Bordetella pertussis induced histamine sensitization (Bphs) controlling susceptibility to histamine-induced pertussis toxin (PTX) sensitization, EAE, and experimental allergic orchitis. Later, histamine receptor H₁ (Hrh1) was identified to be the gene underlying Bphs.
Histamine (HA) (2-[4-imodazole]-ethylamine) is a ubiquitously distributed biogenic monomine that regulates many physiological and pathological functions. HA exerts its effects through binding to four 7-transmembrane G-protein coupled (GPC) histamine receptors (HR), H₁R, H₂R, H₃R, and H₄R. The role of HA in the immunopathogenesis of MS and EAE has been well documented.
H₁R and H₂R are expressed by immune cells and mice deficient for either H₁R (H₁RKO) or H₂R (H₂RKO) exhibit reduced EAE severity compared to wild-type (WT) mice. We have investigated the role of H₁R in EAE susceptibility by re-expressing H₁R in H₁RKO T cells, endothelial cells, and antigen presenting cells (APCs). Our results suggest that the re-expression of H₁R in T cells regulates encephalitogenic responses and its re-expression in endothelial cells protects H₁RKO mice from EAE.
In addition, as discussed in Chapter 3, the re-expression of H₁R in APCs does not contribute to EAE susceptibility or affect encephalitogenic T cell responses. Our results highlight the cell specific effects of H₁R in EAE susceptibility. Furthermore, we have explored the role of H₂R in EAE susceptibility by re-expressing this receptor in H₂RKO T cells and have shown in Chapter 5 that H₂R signaling directly in T cells contributes to EAE susceptibility when induced in the presence of PTX.
Whereas H₁R and H₂R are propathogenic, H₃R and H₄R are antipathogenic in EAE. Therefore, in Chapter 2, we investigated the combinatorial effects of each class of HR on EAE susceptibility by generating double KO mice (H₁H₂RKO vs. H₃H₄RKO). Importantly, our results suggest that the combinational targeting of HRs may be an appropriate disease modifying therapy in MS. In addition, our results suggest there is compensation among HRs, such that in the absence of one or more HRs there is compensatory upregulation of the remaining HRs.
Historically, HA is known to signal through four known GPC-HRs. However, there is evidence for HA signaling through non-GPCRs, like the [upsilon]-aminobutyric acid receptor (GABAaR). In Chapter 4, we show that mice deficient for the four known HRs (H₁₄RKO) exhibit increased resistance to EAE compared to WT mice and histidine decarboxylase deficient mice (HDCKO), which lack systemic HA. Therefore, in light of the opposing results from the HDCKO studies, our data suggest that HA may initiate signaling independently of H₁₋₄R and supports the existence of an alternative HAergic pathway in regulating EAE.