Inflammation booksreviewed by T. Nelson
Reviewed by T. Nelson
It seems like only yesterday that microglia and astrocytes were the dogs of neurobiology. Astrocytes were mere servants at the beck and call of neurons, providing them with nutrients and removing their used metabolites, like waiters pouring their wine and taking away their dirty forks. Microglia were the undertakers, scraping up the spilled guts of dead and mangled neurons, and cleaning away any dirt, bacteria, or other bits and pieces of useless material that somehow got into the brain.
Now the dogs are having their day. The discovery that mutations in TREM2, a protein on the surface of microglia, are an important risk factor for Alzheimer's disease, is one reason. The ability of microglia to transmit pain signals—one of the clearest demonstrations outside of sex hormones of a biochemical difference in the brains of men and women (see here for details)—is another. Microglia gone wild can cause neuroinflammation, they're mad as hell, and they're not going to take being ignored any more.
Microglia don't just sit around waiting for a cell to get injured. They stay in constant surveillance mode. After an injury, ATP and nitric oxide from injured cells cause them to migrate toward the injury.
Their main function is to carry out inflammation. In response to injury they become less ramified and adopt an aggressive amoeboid shape. They secrete cytokines and chemokines to send intercellular signals to each other. There are dozens of these, which makes antibody companies deliriously happy, but in the brain they send complex chemical signals to astrocytes, causing them to activate as well, which (according to some studies) can result in neuronal cell death. Is all this part of the disease process, or are they the brain's attempt to repair itself? So far, nobody knows for sure.
Microglia also do synaptic stripping, where they remove all the synapses from a damaged neuron in order to reduce its firing rate and energy consumption, thereby protecting it while it undergoes repair. The idea is that memories can be re-learned and synapses re-formed, but neurons cannot be replaced. Synaptic stripping also occurs during early development, when the number of synapses in a healthy brain decreases dramatically, and it's microglia that we have to thank for it.
Microglia have long been known to be important in multiple sclerosis and ALS, but it's Alzheimer's disease that's putting their name in lights. Microglia absorb beta-amyloid oligomers and plaques, but not the fibrillar form. Depending on whether they're in M1 or M2 state, they can mercilessly strip all the synapses off a neuron or gently cradle it and nurse it back to health.
The writing style in this multi-author book doesn't exactly put it this way. It's a typical collection of review articles, and the name, year format makes it frustrating to read:
Microglial cell dynamics and morphological 'plasticity' were investigated in slice cultures (Hailer et al. 1996; Dailey and Waite 1999; Stence et al 2001; Grossmann et al 2002; Petersen and Dailey 2004; Kurpuis et al 2006; Grinberg et al. 2011), in isolated cells as well as co-cultures (Ward et al. 1991; Glenn et al. 1992; Rezaie et al. 2002; Ohsawa and Kohsaka 2001), and 'real-time' microglial activation could now be examined (e.g. see Rangroo Thrane et al. 2012). A number of studies also began to examine the behaviour of ramified cells (Ward et al. 1991; Booth and Thomas 1991; Kloss et al. 1997; Eder et al. 1999; Rosenstiel et al. 2001; Rezaie et al. 2002).
But hidden in that mass of unreadable junk there's an exciting and important story. Until microglia came along, Alzheimer research was hopelessly stuck: beta-amyloid was thought to cause the disease, but removing it had no effect. ApoE4 was the biggest risk factor, but all ApoE seemed to do was transport cholesterol. Presenilin mutations seemed to have little consistent effect. The TREM2 discovery has turned the field into a new direction. This book is one of the few out there that gives us solid background information (Wolfgang J. Streit's book is currently 92% off, but it's from 2002, leaving Microglia: Methods and Protocols as the main competitor).
Here's another typical sentence.
Neutrophils and macrophages release highly pro-inflammatory substances, including prostaglandins, lipoxygenases, cytokines, reactive oxygen species (ROS), NO, proteases, and adenosine triphosphate (ATP). . . . Neuron sensitization and activation after injury constitutes a principal pain mechanism. Exogenous administration of such agents (e.g. TNFα, prostaglandin E2 (PGE2)) results in pain hypersensitivity (Fukuoka et al 1994; Jin and Gereau 2006; Ozaktay et al. 2006; Schafers et al. 2003a; von Banchet et al. 2005; Zhang et al. 2002; Obreja et al. 2002, 2005).
It's unlikely that TNFα, IL-1β, IL-6, and nitric oxide are involved in as many things as some of the authors claim. In general you'll need to know a fair amount of molecular biology or neuropathology to make much sense of it and to evaluate which results are valid.
There are chapters on spinal cord trauma, stroke, MS, HIV, pain, aging, learning and memory, development, astrogliogenesis, imaging, immune responses, and the history of microglia. Most chapters have good color figures, lots of references, and good background information. Researchers and graduate students will find it invaluable.
apr 08, 2018
Reviewed by T. Nelson
This one is an excellent, comprehensive textbook on immunology. It covers innate and adaptive immunity, T-cells and B-cells, lymphocyte receptor signaling, complement system, MHC classes I and II, T-cell mediated immunity, viruses, antibodies, the humoral immune response, autoinflammatory diseases, allergy, memory, and immunodeficiency diseases.
The presentation is at an upper undergraduate or graduate school level. There are color diagrams, graphs, and photomicrographs on almost every page. The focus mostly ranges from the cellular to the structural biology level, but there are also many comparisons of different species, especially mouse, but also camels, Drosophila, invertebrates, and cartilaginous fish and agnathans, which have much less sophisticated immune systems than humans. Invertebrates don't have an adaptive immune system (which consists mainly of T cells and B cells) like vertebrates. Emerson on antibodies “A foolish consistency is the immunoglobulin of little monocytes, adored by biologists and divines.” —what Ralph Waldo Emerson would have said if he knew anything about antibodies*
(Warning: spoilers ahead)
B cells and T cells are lymphocytes that start out in the bone marrow. Each cell has a different antibody with a different specificity, so one cell corresponds to one antibody. This is done using a type of evolution that happens on the scale of hours instead of millennia. First the cell rearranges the immunoglobulin DNA by a process called V(D)J recombination. Then, when an antibody is present, the DNA is changed again by somatic hypermutation, in which random mutations are deliberately created. The process is very inefficient, in many cases producing antibody DNA that can't even be translated into protein. To make the antibody even better, the proteins are then converted from IgM to IgG by another DNA rearrangement called class switching. Although B cells get a couple extra chances to make good antibodies, most of them are no good and they get immediately destroyed. Of those that survive, only between 10 and 40% survive to maturity.
Life is even tougher for T cells, which migrate from bone marrow to the thymus, where 98% of them die. Unlike B cells, T cells react only to peptides made from pathogen proteins that are chewed up inside other cells and presented to the T cells on the surface as offerings attached to MHC class I and II proteins. In this way, T cells can detect pathogens inside other cells, and smite the cells if they're infected.
This is called cellular immunity. At the site of infection, dendritic cells ingest samples of the pathogen and return to the lymph nodes, where they use their MHC proteins to inform the T cells about the pathogen, like tiny rat finks. When your lymph nodes are swollen, it is called lymphadenitis, and it means your T and B lymphocytes have migrated there and are proliferating and becoming activated to fight the infection.
On the biochemical level the emphasis in this book is mostly proteins and DNA, with only a few pages on eicosanoids. Cytokines are talked about quite a bit, but other than their names they might as well be magic pixie dust. (In fairness, I know of no book that describes them adequately.) Microglia, lipoproteins, and neuroinflammation are hardly mentioned at all; the emphasis is exclusively on the periphery. Each chapter has a selection of review papers for further reading.
Here are two sample sentences:
Some other receptors that can inhibit lymphocyte activation possess motifs in their cytoplasmic regions that are known as the immunoreceptor tyrosine-based inhibitory motif (ITIM, consensus sequence [I/V]XYXX[L/I], where X is any amino acid) or the related immunoreceptor tyrosine-based switch motif (ITSM, consensus sequence TXYXX[V/I]). When the tyrosine in an ITIM or ITSM is phosphorylated, it can recruit either of two inhibitory phosphatases, called SHP (SH2-containing phosphatase) and SHIP (SH2-containing inositol phosphatase), via their SH2 domains.
As you can see, the presentation is fact-filled and presumes a working knowledge of biochemistry, so most readers will be taking notes or making pathway diagrams to organize the huge mass of information as they go along.
This $175 book is what you must have if you really want to understand the peripheral immune system. This big, 8.4×10.9 inch, 4½ pound, 900 page book is a bit clumsy as a paperback. I'd recommend the hardcover version if you can afford it, but it's more expensive and probably a lot heavier.
Charles Janeway contributed much to our understanding of immunology. See here for a good description.
* Emerson's actual quote: A foolish consistency is the
of little minds, adored by little statesmen and philosophers and divines.
jan 24 2019; edited jan 28 2019
Reviewed by T. Nelson
The brain is notorious for using ordinary molecules for specialized purposes. A good example is histamine, which we associate with hay fever. In the brain, it's a neurotransmitter that's essential for conscious awakeness; this is why small amounts of antihistamines that get into the brain cause drowsiness.
We also know bacteria in the gut can affect our brain. Over 50% of the cells that make up our bodies are microbial, and microbes contribute more DNA than exists in the human genome.
But even more surprising is the discovery that depression may not be a neurotransmitter imbalance as once thought, but a form of inflammation. MDD, or major depressive disorder, is associated with elevated cytokines, CCL2, and other inflammatory proteins in the blood. When monocytes from MDD patients are stimulated with LPS, a bacterial protein that evokes a strong inflammatory response, they produce high levels of interleukins IL-1β and IL-6, indicating that immune cells in depressed patients respond differently from cells in healthy patients.
The idea is that depression is a type of “sickness behavior” that induces the patient to withdraw from others and rest in order to recover from an infection. As such, it should be beneficial, but in MDD patients it goes out of control.
There's also something called depression-associated exhausted state of innate immunity, where depression causes a reduction in the immune response. Different studies have gotten different results, so no one really knows for sure, but something is definitely going on—and not just in depression.
For instance, without TLR5, a toll-like receptor that is part of our immune response, mice develop metabolic syndrome (adiposity, hyperlipidemia, hypertension, insulin resistance). These changes are mediated by altered gut microbiota, which produce endotoxins. It's no surprise that they'd cause inflammation, but the surprise is that being overweight could be caused not by overeating, but by having intestinal bacteria from the wrong side of the tracks.
Even newborn babies are exposed to bacteria before birth, as well as afterward in their milk, which contains sugars the baby can't digest. The milk contains bacteria the baby needs, as well as food for the bacteria.
This book is stuffed with interesting biochemical facts as well, such as that the cofactor of eNOS (an enzyme that makes nitric oxide) is BH4, that Aquaporin 4 (a great name!), the water channel in astrocyte end feet in the blood-brain barrier, may contribute to the antidepressant effects of SSRIs, and that pro-inflammatory cytokines sIL-2R, IL-6, and TNFα are consistently elevated in patients with MDD compared with healthy controls. BH4 (tetrahydrobiopterin) is especially relevant, as it's also required for synthesis of catecholamines such as serotonin and norepinephrine, which are targets for SSRIs and SNRIs.
This is a roundabout way of saying that it wouldn't hurt to have a background in molecular biology and neuroscience before tackling this book. Couldn't hoit.
Not all the chapters require that, though, and there are several non-technical chapters that laymen could learn a lot from as well. The chapter on the genetics of depression describes in simple terms what is meant by a single nucleotide polymorphism, or SNP. It says that even though MDD appears to be inherited, no one has ever found a gene that correlates with it; even GWAS (genome-wide association studies) haven't found much of anything yet.
Even so, this book is written by scientists, not popular science writers, with all that implies. There's lots of repetition—reading all 35 overlapping review articles would cause an immune response of its own. Better editing, and an LOA (list of acronyms), would have helped.
Many people remember the excitement when interferon was discovered. The word interferon first appeared in a comic book, where a character used that famous phrase. It was called a wonder drug. It was a wonder, all right: interferon gave us the clearest demonstration that inflammation can cause depression, and not just correlate with it.
It was quickly discovered that interferon IFN-α, used to treat hepatitis C, causes anxiety and depressive symptoms in 21–58% of patients who receive it. Some get long-lasting and severe MDD within a month of treatment, which can last for years afterward. Even a single exposure to an inflammatory stimulus such as LPS or typhoid vaccine can induce depression, especially in women.
Ironically, though, repeated exposure during childhood protects you: in one famous study, it was found that at the border between Russia and Finland, the Finns have 4× higher childhood atopy (allergic hypersensitivity), while the Russians right across the border have normal atopy but a 6× higher incidence of type 1 diabetes. It's been suggested that the cause is bacteria: the Ruskies have more E. coli, which drives endotoxin tolerance, while the endotoxin in the Finns comes from Bacteroides species, which blocks the effect of the E.coli toxin, thereby depriving the Finns of regulatory T-cell (Treg) induction.
Gut biodiversity alone can reduce the incidence of depression. Diversity improves the balance of short-chain fatty acids like butyric, acetic, and propionic acid, which are created by fermentation of indigestible fiber and strengthen the cells, called enterocytes, in the gut. These molecules, along with plant polyphenols (tannins, flavonoids, phenolic acids, etc) increase Treg. So when your diversity manager tells you to write a statement on diversity and inclusion, this book will give you a golden opportunity to show off your knowledge of intestinal bacteria and inflammatory bowel disorder.
The general feeling, though, seems to be caution: anti-inflammatory agents can relieve depression, but only in patients who have both inflammation and depression. In patients with no inflammation, anti-inflammatory treatment such as infliximab can make it worse. So it's not yet possible to say definitively that depression = inflammation.
But what it does tell us definitively is that the immune system in vertebrates is very, very complicated. Yeh . . . we guessed that already.
jun 30 2018; edited jul 01 2018