Chapter 126
Controlling Our Immune System — 3
Let me provide a brief sketch for how an autoimmune attack might occur. Let’s say a virus, which has an antigen, infects the body. But that antigen is similar to one in the person’s body, a molecular mimicry. Dendritic cells detect the infection and activate T cells that connect to both the viral antigen and the self-antigen, with CD8+ killer T cells destroying the cells infected with the virus antigen and the person’s cells. At the same time, CD4+ helper T cells can activate B cells to release autoantibodies, which attack one’s own proteins. Both the B cells and CD8+ cells evolve to memory B and T cells that can transform the acute response to a chronic autoimmune disease.
Figure 9.2. Schematic of immune cell structure (upper) and population of cell types (lower). Adapted from Philipp Dettmer, Immune (New York: Penguin Random House, 2021); and Ron Sender et al., “The total mass, number, and distribution of immune cells in the human body,” Proceedings of the National Academy of Sciences of the USA 120, no. 44 (October 2023): e2308511120, https://doi.org/10.1073/pnas.2308511120.
In recent years, we’ve seen more evidence that autoimmunity is linked to nutrition. Caloric restriction leads to reprogramming of T cells to be anti-inflammatory and promotes the gut microbiome’s production of anti-inflammatory metabolites. Fasting activates neurons in the brainstem, with a fortuitous redistribution of T cells to the bone marrow and reduction of cytokine production. That inhibits autoimmunity, while obesity promotes it via adipose tissue, which releases cytokines that cause an overproduction of pro-inflammatory T cells and a decline in protective Tregs. Obesity is a known risk factor for several autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Since energy-sensing pathways are so important in modulating the immune response, the possibility of “pseudo-starvation” with drugs like rapamycin or metformin (mTOR inhibitors) has been raised to simulate caloric restriction’s impact on autoimmunity.
Abig discovery in 2024, considered a black swan event, was the rheostat circuitry for how the brain can dial up or down our immune response. By injecting bacteria compounds into the abdomen of mice, a brainstem region was activated. The inflammation signals were transmitted via the vagus nerve to the caudate nucleus soltaris. When these neurons were activated, inflammation was reduced by about 70 percent. In contrast, when the neurons were silenced, an immune response was unleashed. Single-cell sequencing further unraveled two discrete circuits, one for pro-inflammatory and the other for anti-inflammatory molecules. In the mouse model of inflammatory bowel disease, manipulating the circuit led to rip-roaring colitis or protection from inflammation. While not immediately clinically transformative, this work lays the foundation for specific neuromodulation of our immune system in the future.
GENETICS, CHROMOSOMES, AND AGE
Many autoimmune conditions cluster in families, and even more so among identical twins. It isn’t uncommon for people to have more than one autoimmune condition. The genome variants linked to the risk of these conditions have considerable overlap for certain human leukocyte (white blood cell) antigen (HLA) variants, and more than 90 percent are in regulatory regions of the genome (not in genes’ protein coding regions). Indeed, single-cell mapping has identified remarkable overlap of likely causative variants across lupus, rheumatoid arthritis, Crohn’s disease, multiple sclerosis, ankylosing spondylitis, and type 1 diabetes. Many of the autoimmune genetic risk variants have evolutionary origins, representing adaptive responses to pathogens from more than four thousand years ago.