Course Sample – Acute Vs. Chronic Inflammation Part 2


 
 

Next Step: Make Cards on the Automatic Key Concepts, and Vignettes

Remember, the more you automatically know what each sentence means on your test, the better you will do. There are 4 stages in making interpretation more automatic:

  • Stage 1: Unable to Make Pathophysiologic Chronologies in Either Timed or Untimed setting
  • Stage 2: Basic Pathophysiologic Chronologies, but with Significant Gaps
  • Stage 3: Detailed Pathophysiologic Chronology Without Time, but Unable to Consistently Generate PC During Timed Setting
  • Stage 4: Consistent Pathophysiologic Chronologies in Timed Setting

My goal with these vignettes is to help you reach Stage 4. How do you do so?

  • With the Automatic Key Concept cards, you can master the underlying information to move past Stages 1 + 2.
  • Then, with the Vignette/Pathophysiologic Chronology cards, you can teach yourself to make these connections on your exam.

summary of key concepts:

automatic key concepts:

Copy + paste these into your cards, to make these key concepts more automatic.

 

B/T cells – how many antigens can an individual cell recognize? What process allows for this?

Each B and T cell can essentially recognize a SINGLE antigen (rather than a class of antigen). Thus, if you needed to recognize 10 antigens, you would need at LEAST 20 B/T cells (10 of each), since each would only be able to recognize a single antigen

V(D)J recombination allows for this

 

Adaptive immune system – use what it is to explain how many cells would need to comprise it? Why?

To be most effective, the adaptive immune system must recognize ANY antigen that is foreign (and not attack your own body), despite the fact that it hasn’t been exposed to the vast majority of pathogens that it might encounter.

To do this, the immune system essentially:

Creates a HUGE variety of B/T cells that could recognize the vast majority of possible antigens

Selects for the cells that can recognize NON-self antigens

There are ~2 trillion lymphocytes in the human body (comparable in cell mass to the liver or brain; estimated ~37.2 trillion cells in the human body)

 

V(D)J recombination – use what it is to explain what cells perform this / what the point is

Recall that the job of the adaptive immune system is to:

1) Recognize and protect against (ideally) ANY foreign macromolecule, even though it has never encountered said macromolecules before (estimates are ~100 MILLION antibodies are necessary for this task), while simultaneously

2) Avoiding recognizing / attacking the huge variety of molecules/proteins in your own body

Yikes! To accomplish this, the adaptive immune system (specifically B + T cells) uses V(D)J recombination (plus positive/negative selection).

V(D)J recombination: there are a variety of V’s, J’s, and (sometimes) D’s, which are basically parts of the genome. In B and T cells, these segments undergo recombination whereby a HUGE array of V’s, D’s, and J’s are recombined to form unique genes (which then become B cell receptors/antibodies or T-cell receptors) that will recognize foreign things

Remember, each antibody is made up of a heavy chain and a light chain, so the total combinations will be the product of the two. In other words, to get to 100 million, all you need are 10,000 heavy chains, and 10,000 light chains (10,000 x 10,000 = 100 million).

For B cells, for example, some sources say there are ~40 Vs, 25 Ds, 6 Js (the exact numbers don’t matter). If that is true, then if you were to have one of each, you would have 40 x 25 x 6 combinations of a single V, D, and J for a single heavy chain → ~6000 different combinations. In addition to this, when they are recombined, nucleotides are added at random by terminal deoxynucleotidyl transferase (TdT), to generate extra diversity – so not difficult to imagine getting to 10,000+ possible combinations.

The light chain has the same choices, although it doesn’t use D’s, so there are 40 Vs and 6 Js → 40 x 6 = 240 different combinations (with many more possibilities due to added nucleotides that are added at random in-between).

 

Alternative complement activation – use what this is to explain whether this would be part of the innate or adaptive immune systems?

C3 complement (like lots of mini grenades) is made by the liver in large quantities → high quantities in blood → constantly undergoes spontaneous cleavage → binds to ANY nearby cell surface, with human cells having mechanisms to inactivate it → disrupt membranes of bacteria/fungi/other invaders

This is an example of INNATE immunity, since rather than recognizing a specific antigen (adaptive immunity), it recognizes a CLASS of antigen (in this case, it recognizes basically any non-human cell membrane)

 

Long double-stranded RNA sequences – how is this recognized by the immune system? Would this be innate or adaptive immunity?

Long double-stranded RNA – human cells only have short sequences of double-stranded RNA. RNA viruses often produce LONG double-stranded RNA chains during replication, which can be detected by TLR3

INNATE immunity – recognizes a CLASS of antigen, in this case double-stranded RNA

 

Unmethylated CpG DNA – how common is this in humans? Why? How about in pathogens?

Most human CpG (e.g., any DNA sequence with __CG___ in it) is methylated → silencing of transcription

However, in bacteria and double-stranded DNA viruses, most CpG sequences are NOT methylated → very good indicator of foreign invader

 

Unmethylated CpG DNA – how is this dealt with in humans? Is this an example of innate or adaptive immunity?

Unmethylated CpG DNA – human cells usually will methylate CpG sequences. Double-stranded DNA viruses, however, do NOT usually do this → recognized by TLR9 → activates immune system

INNATE immunity – recognizes a CLASS of antigen, in this case unmethylated CpG DNA

 

Adaptive immunity – use what it is to give examples of how foreign invaders are recognized

Adaptive immunity = antigen-specific immune response

 

Vaccines – how do these work generally?

Foreign antigen(s) introduced to body (e.g., killed virus, mRNA → protein production via cells, etc.) → B and/or T cells that recognize that particular antigen will increase in number; may form memory cells to respond more quickly/effectively to future invasions; and in the case of B cells create higher-affinity antibodies (somatic hypermutation)

Vaccines – would this take advantage of innate or adaptive immunity primarily? Why?

Adaptive immunity – in this case the B/T cells that recognize a SPECIFIC antigen (rather than a class of antigens) will expand and/or increase their affinity for that antigen, forming memory cells

 

Microscopically, what inflammatory cells are most abundant histologically 24 hours post-MI? Why does this make sense?

Neutrophils – these are cells mediate innate acute inflammation. 24 hours after an infarction, this is still ACUTE inflammation → neutrophils most abundant

NOTE: this is one of the reasons that the histopathology of myocardial infarctions is such a big deal for USMLEs (especially Step 1). Not only is heart disease hugely clinically important, but it represents a FANTASTIC model for understanding the general process of acute vs. chronic inflammation and response to injury

 

Microscopically, what inflammatory cells are most abundant histologically 3 days post-MI? Why does this make sense?

Macrophages – these cells mediate innate chronic inflammation. Starting at 3 days, this is where the transition between acute and chronic inflammation occurs → macrophages most abundant.

 

Fibrosis – use what this is to explain whether it is normal or pathologic. What generally is it associated with?

Fibrosis = pathological wound healing where normal tissue is replaced with connective (scar) tissue. Recall that during inflammation, the ECM must be repaired/replenished. Thus, fibrosis is essentially the excessive deposition of ECM seen in chronic inflammation.

Theme: fibrosis – like sepsis and anaphylaxis – is simply a normal aspect of inflammation that is taken to the extreme (in this case, due to chronic inflammation)

 

Generally, what causes precipitation of things in the body?

Solute ↑

Solvent ↓

Solubility change (e.g., pH, chemical structure changes, etc.)

Rock candy – how is this an example of precipitation?

Water is saturated with sugar (solute ↑) and heated (solubility ↑). Then it is cooled, with a lollipop stick placed in the solution.

As it cools → temperature ↓ → solubility of sugar ↓ → sugar precipitation on stick → forms sugar crystals (rock candy)

 

Kidney stones – using your understanding of what causes precipitation, explain how to prevent kidney stones

Things causing precipitation in the body:

Solute ↑

Solvent ↓

Solubility change (e.g., pH, chemical structure changes, etc.)

To prevent kidney stones, patients are told to drink (lots of) water. Drinking water → water (solvent) in blood ↑ → chance of precipitation of stones ↓

 

Metastatic calcification – use the general causes of precipitation to explain what this is

Things causing precipitation in the body:

Solute ↑

Solvent ↓

Solubility change (e.g., pH, chemical structure changes, etc.)

In metastatic calcification, there is either too much calcium and/or phosphate (”solute”) in the serum → precipitation

(Side note that sometimes comes up in clinical practice: some guidelines suggest trying to keep the ”calcium-phosphate product” – multiplying the serum calcium x serum phosphate (in mg/dL) below 55)

 

Dystrophic calcification – use the relative intracellular/extracellular concentrations of calcium and phosphate to explain how this could occur

Recall that:

Things precipitate when there is too much solute / too little solvent / solubility change

Calcium is HUGELY more abundant outside the cell than inside (20,000-100,000x); the reverse is true for phosphate (~100x)

In cell necrosis → cell membrane integrity disrupted → calcium from outside allowed to enter the cell → will precipitate with the high intracellular phosphate

 

Dystrophic calcification – is this more associated with acute or chronic inflammation? Why would this make sense?

Chronic inflammation. The innate immune system – and macrophages specifically – can both contribute to causing dystrophic calcification (presumably through damage) as well as clearing it (via demineralization and presumably its general role as a phagocyte).

In chronic inflammation – and the constant damage that accompanies it – it would make sense that the dystrophic calcification would continue to accumulate (since it would overwhelm macrophages’ abilities to demineralize it)

 

What does the following image represent – chronic pancreatitis or acute pancreatitis? How do you know?

Chronic pancreatitis (see all the calcifications!!)

Chronic damage / inflammation → chronic disruption of cellular membranes → high extracellular calcium continues to precipitate with the high intracellular phosphate → over time, innate immune system unable to clear the mineralized product → dystrophic calcification

(For more on how x-rays work / why calcification shows up white on x-ray/CT, see Cardiovascular Vignette #11)

 

Granuloma – definition?

“Chronic inflammatory reaction characterized by the focal accumulation of activated macrophages, often with an epithelioid appearance.” (Robbins)

In essence, it is chronic inflammation with activated macrophages called epithelioid cells

 

Mnemonic for the differential diagnosis of non-caseating granulomas – rather than memorizing this, what concept could you use to understand this (and predict even more conditions than are listed)?

Something foreign that your body can’t clear → chronic inflammation +/- adaptive immunity → granulomas

 

Inflammation – how targeted is this, generally? Use neutrophils/macrophage killing as an example.

As a general observation, inflammation → lots of collateral damage, including DNA damage → high cell turnover

As a simple example for how inflammation → lots of collateral damage, consider that neutrophils/macrophages generate reactive oxygen/nitrogen species as part of the process of killing microbes.

Inflammation – even adaptive immunity – has been likened to killing a mosquito with a machete. You may kill the mosquito, but most of the blood on the floor will be yours.

 

Chronic inflammation – how strong of an association is there with cancer? What are some proposed associations?

Very strong. There are LOTS of proposed mechanisms, including:

Inflammation → non-specific damage → DNA damage + cell turnover ↑ → rapid accumulation of mutations

Inflammation → extracellular matrix degradation → ease of invasion of tumor cells ↑

Macrophage migration inhibitory factor (MIF) from macrophages / T cells → enhanced immune response + p53 suppression → accumulation of mutations ↑

 

 

references:

Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Lymphocytes and the Cellular Basis of Adaptive Immunity. https://www.ncbi.nlm.nih.gov/books/NBK26921

Eveleth, R. There are 37.2 Trillion Cells in Your Body. Smithsonian Magazine; 2013.  https://www.smithsonianmag.com/smart-news/there-are-372-trillion-cells-in-your-body-4941473/

VDJ recombination.png. (2020, September 26). Wikimedia Commons, the free media repository. Retrieved 20:43, July 8, 2021 from https://commons.wikimedia.org/w/index.php?title=File:VDJ_recombination.png&oldid=471622614.

Antibody basic unit.svg. (2020, November 1). Wikimedia Commons, the free media repository. Retrieved 20:44, July 8, 2021 from https://commons.wikimedia.org/w/index.php?title=File:Antibody_basic_unit.svg&oldid=509177891.

Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028-1040. Published 2012 Jul 6. doi:10.1038/nm.2807

Sinha, M., Sen, C., Singh, K. et al. Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. Nat Commun 9, 936 (2018). https://doi.org/10.1038/s41467-018-03208-w

Rock-Candy-Sticks.jpg. (2020, October 27). Wikimedia Commons, the free media repository. Retrieved 22:30, November 7, 2020 from https://commons.wikimedia.org/w/index.php?title=File:Rock-Candy-Sticks.jpg&oldid=503316499.

Zander, Dani & Farver, Carol. (2017). Pulmonary Pathology: A Volume in the Series: Foundations in Diagnostic Pathology.

Wei M, Taskapan H, Esbaei K, Jassal SV, Bargman JM, Oreopoulos DG. K/DOQI guideline requirements for calcium, phosphate, calcium phosphate product, and parathyroid hormone control in dialysis patients: can we achieve them?. Int Urol Nephrol. 2006;38(3-4):739-743. doi:10.1007/s11255-005-0083-x

Goretti Penido M, Alon US. Phosphate homeostasis and its role in bone health [published correction appears in Pediatr Nephrol. 2017 Jul 6;:]. Pediatr Nephrol. 2012;27(11):2039-2048. doi:10.1007/s00467-012-2175-z

Demaurex N, Nunes P. The role of STIM and ORAI proteins in phagocytic immune cells. Am J Physiol Cell Physiol. 2016;310(7):C496-C508. doi:10.1152/ajpcell.00360.2015

Clapham DE. Calcium signaling. Cell. 2007;131(6):1047-1058. doi:10.1016/j.cell.2007.11.028

Rogers MA, Aikawa M, Aikawa E. Macrophage Heterogeneity Complicates Reversal of Calcification in Cardiovascular Tissues. Circ Res. 2017;121(1):5-7. doi:10.1161/CIRCRESAHA.117.311219

Chronische Pankreatitis mit Verkalkungen – CT axial.jpg. (2021, February 14). Wikimedia Commons, the free media repository. Retrieved 22:47, July 9, 2021 from https://commons.wikimedia.org/w/index.php?title=File:Chronische_Pankreatitis_mit_Verkalkungen_-_CT_axial.jpg&oldid=532623269.

Granuloma mac.jpg. (2020, October 12). Wikimedia Commons, the free media repository. Retrieved 19:52, July 9, 2021 from https://commons.wikimedia.org/w/index.php?title=File:Granuloma_mac.jpg&oldid=487433909.

Mehta, Atul & Ali, Syed Rizwan. (2017). Mnemonic for the differential diagnosis of non-caseating granulomas. Sarcoidosis, vasculitis, and diffuse lung diseases: official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders. 34. 200. 10.36141/svdld.v34i2.5674.

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-867. doi:10.1038/nature01322

Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments