Medical School 2020, Year 2, Week 5

From our anonymous insider…

Hematology and immunology. Immunology is one of the class’s least favorite topics. Gigolo Giorgio: “I accept just taking a hit on the exam. It makes no sense to me.”

An enthusiastic 39-year-old immunologist kicked off the lectures. She explained, “We need about 100 million unique antibodies to be immune competent. We have about 30 billion B cells in the blood. That means we only have 300 potential B cells that need to become activated if we are to mount an antibody attack against a given antigen. This is the key dilemma in adaptive immunity: How do you find them!”

Our first-year perspective on the immune system was cell-centric. This week we learn that the story is more complex and includes smaller-scale proteins from the complement system and larger-scale tissues such as the spleen filtering blood-borne pathogens.

Our current understanding of a typical bacterial infection:

1. The innate immune system recognizes common pathogens. Complement proteins (smaller than cells and made by the liver) mark bacteria for opsonization (trigger for phagocytosis or cellular ingestion).
2. Resident macrophages (cells) phagocytose (ingest) marked intruders resulting in an inflammatory “cytokine storm”. This causes systemic changes such as fever and increased production of immune cells in the bone marrow (lymphocytosis) and local changes such as blood vessel dilation to increase tissue perfusion and neutrophil infiltration into the tissue.
3. Neutrophil infiltrate the inflamed tissue. Neutrophils, the most abundant leukocyte (white blood cell), are the immune system’s pawns that kill bacteria by eating them and producing high concentrations of hydrogen peroxide in the phagosome (walled off vesicle containing the bacterial cell inside the neutrophil). After the neutrophil has worn itself out, it will explode in a process called netosis. The neutrophil’s DNA acts like a spider web (called neutrophil extracellular traps) to prevent the bacteria from escaping the site of inflammation. Pus is dead bacteria and dead neutrophils.
4. Adaptive immunity activated (if needed).
5. If necessary, the spleen will filter bacteria in the blood (bacteremia) through small capillary beds called sinusoids.

The C3 protein is fundamental to the complement system and will bind to almost any biological molecule. How does the body avoid its own proteins being marked for phagocytosis? The liver releases anti-complement factors that bind to sialic acid, a component on human cell membranes. Streptococcus pyogenes, the bacterial strain causing strep throat and necrotizing fasciitis, expresses M protein to mimic sialic acid. The immunologist explained, “Although this molecular mimicry decreases the efficacy of the innate immune system, it is also Strep’s greatest weakness.” Our adaptive immune system readily produces antibodies that target M protein. The problem is that this antibody can cross-react with our own tissue causing a rare complication of sore throat: rheumatic fever (inflammatory disease that leads to skin rash, joint pain, and destruction of heart tissue).

If the innate immune system mechanisms are insufficient for clearance, the adaptive immune system will be activated. Resident macrophages will migrate to lymph nodes and present phagocytosed segments of foreign material on major histocompatibility complex (MHC) proteins to lymphocytes (T cells and B cells) that circulate among lymph nodes. Because the body can’t anticipate all of the epitopes (protein shapes) we might encounter, we use a game of probability. The immunologist explained, “We are finally unlocking the adaptive immune system. When I was an undergraduate in the late 80s, how our adaptive immune system generates this antibody diversity was still not accepted let alone in textbooks. MIT Professor Susumu Tonegawa won the Nobel Prize for discovering VDJ [variable, diversity, and joining] recombination. He showed that each B and T cell mutates its own DNA to rearrange the genes encoding the B cell’s antibody or T-cell receptor. Each B and T cell clone has different DNA than your typical cell in your body! If this B cell antibody or T cell receptor recognizes a sequence presented on MHC, it will become activated. The activated cell will undergo clonal expansion [reproduction by division], and, in the case of B cells, will differentiate into a plasma cell secreting gobs of antibody against this specific antigen into the bloodstream.”

Our patient case: Georgia, a 46-year-old female presenting to her internist for a routine physical. Medical history is unremarkable except for well-controlled hypothyroidism. She has swollen lymph nodes (lymphadenopathy) in her neck. Routine blood tests reveal elevated protein. Serum protein electrophoresis, a technique that separates proteins based upon electric charge, reveals an “M-spike” in the immunoglobulin (antibody) zone, suggesting an increase in concentration of a single clonal variant of immunoglobulin. “Georgia had a rogue plasma cell producing gobs of a single type of antibody. It is essential you understand the significance of clonal expansion to her condition versus the antibody response to an infection. During an infection, several B clonal species will get activated, each with a different antibody that binds to different sites of a pathogen. Infection causes a general increase in globulin concentration but not a spike.” The risk is as this single clonal variant continues to expand, it could push out the normal functioning bone marrow cells.

Georgia was referred to heme/onc (hematology/oncology) for further evaluation for this monogammopathy of unknown significance. One of my favorite lecturers, the young redheaded hematologist, followed Georgia for one year during which she began to have anemia, proteinuria (protein in urine), and bone lesions on routine tests. George was diagnosed with multiple myeloma (MM) at the age of 47 and, based upon her genetics and stage, given eight years to live. (Type-A Anita uses the helpful mnemonic “CRAB” to remember the classical signs of MM: hyperCalcemia, Renal impairment, Anemia, Bone lesions.) After her diagnosis, she quit her job as a secretary for a law firm and went on disability.

Georgia underwent several weeks of intense chemotherapy and a successful autologous hematopoietic stem cell transplant (HCT) over the course of a month-long hospital stay. She explained, “I never considered that I would die during the treatment.” She is now two years into remission and maintains an active life.

The HCT given to Georgia is the gold standard for MM treatment. “Why do we even give bone marrow transplants to MM patients?” asked the hematologist. She answered her own question: “The purpose of a bone marrow transplant is to be able to give higher doses of chemotherapy that would otherwise be lethal. We nuke the patient.” The hematologist recounted how bone marrow transplants were first investigated after the observation that individuals exposed to radiation from Hiroshima and Nagasaki developed pancytopenia (low blood cell counts). Bone marrow transplants were thought up as a way to reverse this aplastic crisis. “Leave it to the DoD to advance science. Pretty quickly oncologists applied the research to cancer treatment.”

“The scariest part of multiple myeloma is that you are never cured,” explained Georgia, as she broke into tears. “It will come back every time. This tragic fact makes MM different from other cancers. I go to an MM support group every two months as opposed to a more general cancer group. It is such a different beast.” Georgia grew up in a large mid-West family with five siblings. “My closest sister withdrew from me after the treatment. I think it is just hard for her to accept.”

The hematologist added, “Plasma cells are the cockroaches of the immune system. They survive everything. The unfortunate truth is that the question is not if MM will relapse, but when. Further, the traditional chemotherapy we use causes the plasma cells that do survive to have more mutations. Drug resistance develops after successive relapses.” She gave an impassioned speech on the importance of research. “The life expectancy for MM has increased dramatically. Maybe ten years ago, Georgia would have had to be maintained on melphalan [nasty chemo agent that acts via a similar mechanism to mustard gas] to contain her MM.” She turned to Georgia: “Could you imagine being on melphalan, the drug used during your bone marrow transplant experience, routinely?” “Oh, God, no. My hair, the diarrhea, the sheer pain. Mostly my hair though.” The class chuckled, and the hematologist continued, “This is changing because of the extraordinary advancements in targeted therapeutics. I love this field because it changes so quickly. Cancer years are dog years. A five-year-old article or clinical trial is thirty-five years old by my standards. Even the current issues of journals are a year late; you have to go to conferences to learn about the latest breakthroughs. It is frankly hard to stay up to date on every neoplasm [cancer]. The result is that oncologists convey out of date survival expectancy to patients.”

Jane had a slight hiccup with her mentee: the day after their first meeting, rumors surfaced that her mentee had disenrolled for personal reasons. The whole class joked that Jane made the helpless M1 quit. “What did you do to her!?!” We never learned the truth, but this classmate was quickly replaced by someone from the waitlist who became Jane’s new mentee: “Rebecca,” who had majored in electrical engineering at a large public university. Rebecca had spent a week at a DO (Doctor of Osteopathic Medicine) school: “I got a call from an unknown number. When I heard I got into this school, I almost fainted. My legs went weak. I packed everything back up and drove the next day eight hours. I really want to call my undergraduate prehealth advisor who told me I would never get into medical school because of my grades. Suck it!” An M1 told Jane, “I like your new mentee better than your last. Thanks!”

Statistics for the week… Study: 15 hours. Sleep: 8 hours/night; Fun: 1 day. Example fun: Dinner party with classmate and his wife, a marriage counselor. “My favorite patients at my old job were the couples with a schizophrenic.” A classmate who worked on a psych ward before matriculating at medical schools said, “Wow! I was scared out of my mind. I had this one patient who would say, ‘There is a woman standing behind you.’ I believed her! I could never do psychiatry.”

More: http://fifthchance.com/MedicalSchool2020