Unraveling the Causes of Canine Immune-Mediated Hemolytic Anemia
Immune-mediated hemolytic anemia (IMHA) is a disease in which the immune system attacks and destroys red blood cells. The resulting anemia causes non-specific clinical signs such as weakness, lethargy, and pale gums or jaundice. The immune malfunction is believed to be improper recognition of self versus non-self (molecules of one’s own body versus foreign molecules such as bacteria or viruses that must be eradicated). However, the exact mechanism of disease development in dogs is poorly understood. Therefore, AKC Canine Health Foundation (CHF) funded investigator and former CHF Clinician-Scientist Fellow, Dr. Steven Friedenberg and his team at the University of Minnesota are studying gene expression in dogs with IMHA (CHF Grant 02348: Whole Blood Transcriptome Profiling of Dogs with Immune-Mediated Hemolytic Anemia (IMHA)). By comparing the genes expressed in dogs with newly diagnosed but untreated IMHA versus those expressed in healthy dogs, they hope to identify specific genes that are turned on early in disease development and can be used as treatment targets.
(Read more about CHF’s Clinician-Scientist Fellowship Program at akcchf.org/clinsci.)
What is gene expression?
Gene expression describes how instructions from a gene (sequence of DNA) are used to create a functional product such as an enzyme or protein. The first step in this process is transcription – where an RNA copy of the gene’s DNA sequence is created. This copy, known as messenger RNA (mRNA), then moves from the cell nucleus to the space within the cell but outside the nucleus, known as the cytoplasm. Within the cytoplasm, mRNA shuttles genetic information around the cell to direct creation of the desired product. This mRNA can be studied and measured in a process known as transcriptome analysis.
Investigators hypothesized that genes and pathways related to immune system function would be altered in dogs with IMHA. Indeed, they found that affected dogs had increased expression of genes related to neutrophil function (a type of white blood cell), coagulation, cell cycle regulation, and red blood cell creation.1 The most overexpressed gene identified regulates programmed cell death for red blood cells - a process that eliminates cells from the body once they become old or damaged, thereby preventing the accumulation of dangerous, abnormal, and even carcinogenic cells. Malfunction of this process could certainly contribute to the development of IMHA.
Surprisingly, affected dogs also had decreased expression of genes related to lymphocyte function (another type of white blood cell). One would expect white blood cells to be hyper-activated in an autoimmune disease state. However, investigators note that activation of these immune cells could vary over time and/or they may only be hyperactivated within organs such as the liver and spleen and not in the blood stream as studied here.
Additional study is needed to confirm how the gene expression and affected enzyme pathways identified in this study contribute to the development of IMHA in dogs. Investigators could also explore how gene expression varies over time from health to early disease to late stage disease. This information will help veterinarians identify disease earlier and provide targets for intervention to prevent and treat this common canine disease. Learn more about CHF’s research to prevent, treat and cure canine disease at akcchf.org/research.
1. Borchert, C., Herman, A., Roth, M., Brooks, A. C., & Friedenberg, S. G. (2020). RNA sequencing of whole blood in dogs with primary immune-mediated hemolytic anemia (IMHA) reveals novel insights into disease pathogenesis. PLOS ONE, 15(10), e0240975. https://doi.org/10.1371/journal.pone.0240975
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