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The intricacies of immune system & novel diagnosis methods

Amidst the bustle of everyday life, we fail to appreciate the remarkable work done by our body’s immune system in keeping us safe during a hectic day’s work or a lazy day’s rest. The immune system is analogous to a nation’s armed forces, and never ceases its vigilance. It comprises an intricate communication network of immune cells that follow efficient strategies to protect us from attack by pathogenic intruders. But, what if our defence system overreacts?

Within the hallowed halls of the IISc campus is a lab that addresses such questions. Led by Prof. Dipankar Nandi, the group focuses on demystifying the intricacies of mammalian immune responses and the problems that arise when they malfunction.

When the body is assailed by viruses, bacteria or parasites like the malarial plasmodium, cells infected by these invaders release chemical signals to alert the immune system. Cytokines are one of a complement of such important chemical signals. A red, itchy bump after a mosquito bite is a visible sign of an immune response to a foreign substance introduced into our bodies.

Cytokines are key mediators of inflammation, which is the first and generally immediate response of our body against any alien agent. However, if an inflammatory reaction is too strong, it can damage our own cells. Sepsis is a potentially life threatening complication of an improperly strong, over-reactive immune response. Sepsis occurs when signaling molecules released into the bloodstream to fight a perceived infection trigger inflammatory responses throughout the body. This inflammation can trigger a cascade of devastating events that can damage multiple organ systems, which can eventually lead to death. One of the key ways of successfully treating sepsis is prompt and accurate diagnosis of the condition.

In a recent bout of research, Prof. Nandi’s lab, in collaboration with Prof. Umapathy’s lab in the Inorganic and Physical Chemistry (IPC) Dept in IISc, has shown that Fourier Transform Infrared spectroscopy (FTIR) can be used to diagnose sepsis in mice. Samples exposed to infrared radiation absorb the radiation in different ways or patterns. This allows FTIR to identify various molecules in the sample via their unique FTIR spectra.

Researchers first induced a sepsis-like condition in mice by injecting them with Salmonella Typhimurium or lipopolysaccharide (or LPS, a toxin from bacterial cell walls that induces shock in mammals).The mice injected with S. Typhimurium formed the ‘infection model’ and those injected with LPS formed the ‘endotoxic shock model’. These two models mimicked a peritonitis-induced condition where infection and inflammation are initiated in the peritoneum (the smooth membrane that lines the abdominal cavity) but quickly spread to other organs, manifesting a sepsis like condition. Then the researchers created a third model of inflammatory peritonitis called a “sterile model” by injecting mice with Thioglycollate (TG). Now, the organs and sera of all these groups of mice were compared with each other using FTIR spectroscopy.

FTIR spectroscopy revealed several major differences in the blood and organs of the different groups of mice. The researchers observed a sepsis-like burst of inflammatory cytokines in the infection and shock models. This was accompanied by a decrease in blood glucose, leukocyte counts, body temperature and respiration rate in mice. A majority of mice in these two models died within 24-40 hr post injection. In the infection model, the drop in glycogen in liver and sera was early whereas it occurred later in the shock model. Also, no significant lipid oxidation was observed in the shock model in the liver. In TG-injected mice – the sterile peritonitis model – there was no burst of inflammatory cytokines and the survival was 100%.

The researchers further compared the changes observed in the liver in the infection-induced sepsis model with those in a drug-induced hepatotoxicity model from one of their previous studies. The results revealed two molecular changes specific to infection-induced sepsis. First, there was a decrease in the protein/lipid ratio; and second, there was an increase in triglycerides, esters and lipid oxidation in the infection model, as compared to the hepatotoxicity model.

This study demonstrated the use of FTIR as a comparative diagnostic tool to detect disease specific changes. FTIR can be used to diagnose sepsis patients at different stages of disease progression. Currently, clinical studies are being performed in using FTIR as a diagnostic tool for humans suffering from sepsis. Clearly, Prof. Nandi’s and Prof. Umapathy’s labs have made an important contribution towards better diagnosis of a potentially fatal disease.