IMM250S Lecture 1 Segment 2 History of Immunology
Liliana immune system is a system of tissues, cells and soluble products that recognize, attack and destroy entities that can threaten our health when they enter our bodies
Major classes of pathogens
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The immune system must recognize and respond to pathogens
Stages of the immune response
Entry of a pathogen
Recognition
Return to resting
Associated challenges
Pathogens are highly varied in structure Mutate and evolve relatively quickly
Pathogens replicate or produce toxins quickly Infection can occur anywhere in the body
Immune-induced disease (immunopathology)
Ø Collateral damage to healthy tissues caused by an
immune response
Mechanisms of defense against infection
Innate Immunity (Rapid, might block
Infection at its start) Innate Immunity
(Adaptive Immunity Slower, provides memory)
Epithelia, mucus
Phagocytes, complement Adaptive Immunity
• Immunitas = to be exempt from (Latin)
• OriginallyreferredtoRomansenators being exempted from public service and legal prosecution
• How did it come to mean ‘exempt from illness or disease’?
Note: Lots of names and dates in the following slides, no need to memorize everything but we expect you to be able to associate a major discovery with the correct researcher
The foundations of immunology:
some questions over the past few hundred years
First ‘concept of immunity’ in the context of disease
“Yet it was with those who had recovered from the disease that the sick and the dying found most compassion. These knew what it was from experience and had now no fear for themselves; for the same man was never attacked twice – never at least fatally.”
• Thucydides, History of the Peloponnesian war, reporting on the war between Sparta and Athens, 430 B.C.
• term ‘immunity’ is not yet used; no concept of causes of disease
https://commons.wikimedia.org/wiki/File:Peloponnesian_war_alliances_431_BC.png
The Black Death, one of the deadliest pandemics in human history
Infection and immunity have shaped the course of history
“Any promise of redemption or resurrection is absent in this painting. Skeletons are sounding the knell, and there is no hope. “
From: Infectious Diseases and Arts
Encyclopedia of Infectious Diseases: Modern Methodologies, by M.Tibayrenc Copyright © 2007 & Sons, Inc.
“The triumph of death” by the Elder (1526/1530–1569) – Museo del Prado. via Wikimedia Commons
The Black Death (plague)
• Seems to have originated in Central Asia in the regions around the Caspian sea, travelled along the trading routes to India, China and eventually reached Europe: a pandemic.
• Responsible for killing 30-60% of all Europeans from 1350-1400
• Europe’s population did not recover until 1550.
• The disease is caused by Yersinia pestis. Humans are infected after being bitten by rodent fleas or by handling infected rodents. Human-to-human transmission spreads the disease
• Still endemic in some tropical and sub-tropical countries, the disease can be controlled now with antibiotics.
Illustration by Deittrich von Lichtensteig from the Toggenburg Bible of Rudolf von Ems https://images.app.goo.gl/hgc1auYHC8svA5h86
Eyam, England, ‘The Plague Village’ (1665-1666)
“Coronavirus: What can the ‘plague village’ of Eyam teach us?”
, professor in biomedical Sciences at the University of Manchester, said: “Learning about our history with disease informs our future. We know the immune system combines with other factors – the strength and dose of the pathogen, the health of the individuals, relative isolation – to determine the severity of the epidemic.”
“Some factors – living in proximity to animals and affecting animal habitats – still play a role today with diseases like Zika, SARS, and coronavirus being shown to originate in animals ” “While many diagnostic details are missing, Eyam is a snapshot of how one community was shaped by – and itself shaped – the spread of a disease.
https://www.bbc.com/news/uk-england-derbyshire-51904810
SMALLPOX – AN ANCIENT SCOURGE
• Caused by Variola major, a human virus with no animal reservoir
• Caused eruption of small fluid-filled vesicles on the skin (pocks), death, extended scarring and blindness in survivors.
• Recorded as early as 1000 B.C. in India, reported also in Ancient Egypt and China.
• Introduced in Europe in Medieval times, it ravaged the population with repeated epidemics. About 1/3 of people infected with it were killed in Europe (1700s)
Europeans brought sickness to the
• Smallpox (and other infectious diseases) was brought to Americas by explorers in 15th and 16th centuries and devastated the Indigenous populations since they had no immunity. Helped the conquest of Mexico by Spanish colonists.
Smallpox affected the American revolution
• 1776: Outbreak of smallpox that badly disrupted American colonial forces assaulting Quebec, Canada, at the start of the American revolution against the British forces. 5000 American soldiers contracted smallpox. The outbreak is considered an important contributing factor in the American defeat in the battle of Quebec.
Aztec people of Mexico dying of smallpox introduced by the Spaniards. Private Collection/ .
http://www.sciencemag.org/news/2015/06/how-europeans-brought-sickness-new-world
Movie: Washington Makes the Call to Inoculate
https://www.history.com/news/smallpox-george-washington-revolutionary-war
The Death of General Montgomery in the Attack on Quebec, December 31, 1775, . Photo credit: Yale University Art Gallery
The practice of variolation: ‘The Royal Experiment’
In the 1700s in Europe up to 400,000 people a year were dying of smallpox
• Introduction of ‘variolation’ in England, urged by Lady Mary
• Variolation: the inoculation of someone with material from a smallpox (variola) pustule to produce immunity to the disease
• Lady Montagu’s advocacy resulted in a trial of variolation conducted by the royal doctor on a group
of prisoners and orphans. All prisoners survived and the procedure deemed safe to be performed on members of the royal family
• Variolation became popular amongst aristocratic and common people
National Library of Medicine, USA
BUT variolation remained dangerous; accidental use of virulent strains resulted in spread of disease and even death (1-2% of cases, against the 20-50% who died by getting the disease naturally). Could also pass other blood-borne diseases
: paving the way for vaccination
• Milkmaids often did not contract smallpox.
• They were exposed to cowpox during their milking duties
• Cowpox is related to smallpox but less virulent
• Does cowpox convey protective immunity against smallpox?
Primer to The Immune Response, 2e. Copyright © 2014 Elsevier Inc.
In 1796, inoculated a young boy with the pus from the cowpox blisters of the hand of a milkmaid to test this hypothesis. James developed a slight fever but nothing more. When Jenner exposed James to variolation, James did not develop symptoms, suggesting that James had acquired immunity via cowpox inoculation.
’s experiment on
Jenner’s smallpox immunization technique was quickly adopted in Europe and North America. In 1853 inoculation with cowpox of infants became compulsory in England.
Drawings showing smallpox and cowpox inoculation. Wellcome Library, London.
Variolation vs Cowpox Inoculation
Further advances in immunization would require an understanding of mechanisms
• About 1800 – first successful immunization (Jenner’s cowpox)
• still no understanding of germs or infectious disease (disease was believed to be caused by ‘bad humors’)
• still no understanding of immune response
• no progress in immunization against other diseases
Microorganisms had been discovered long before by Antonie van Leeuwenhoek around 1650. But more than a century had to pass before the first connections between germs and infectious disease was made. http://www.hhmi.org/biointeractive/seeing-the-invisible
A century after Jenner: The “Germ Theory of Disease”
• , and others began to isolate and characterize organisms that could only be seen under a microscope. The Germ Theory of Disease was proposed and proved between 1850 and 1920
• ‘microbes’ are organisms too small to be seen by eye, and some cause specific diseases: pathogens
• Koch discovered that anthrax was caused by a bacteria he named Bacillus anthracis, and and later discovered the agent causing tuberculosis (M. tuberculosis)
• a given pathogen causes a specific illness (Koch’s postulates, next lectures ). Koch developed techniques for growing pure cultures of bacteria
National Library of Medicine, USA
Wikimedia Commons
(1880s) extended the immunization approach of Jenner: “attenuated” germ cultures
• Used attenuated (spoiled) cholera cultures and determined he could induce acquired immunity in chickens to virulent cholera
• The same held true for cattle anthrax, and rabies (with )
Pasteur made other important discoveries:
• Fermentation
• Disproval of the ‘spontaneous generation of germs theory’
• Pasteurization
9-year old , the first person vaccinated against rabies
http://www.pasteur.fr/en/institut-pasteur/history/louis-pasteur/louis-pasteur-s- work/middle-years-1862-1877
vaccines are born!
Pasteur’s experiment disproving the spontaneous generation of microorganisms
Before you proceed with Lecture 1 Segment 3
• Quercus Discussion prompts:
• Why was Jenner’s vaccine superior to variolation?
• What was the significance of ’s experiment of inoculating chickens with spoiled cholera cultures?
IMM250 Lecture 1 Segment 3 Modern Immunology
The Immune System: An Overview
How does immunity work to protects us from infection?
Cellular versus humoral immunology:
A century-long dispute
Antibodies
“I fetched from it a few rose thorns and introduced them at once under the skin of some beautiful starfish larvae as transparent as water.
I was too excited to sleep that night in the expectation of the result of my experiment and very early the next morning I ascertained that it
had fully succeeded. That experiment formed the basis of the phagocyte theory to the development of which I devoted the next 25 years of my life….”
Metschnikoff, E. 302, 31.12 (1908).
Immunity and the Invertebrates Scientific American November 1996
What protects us from infection? Cells!
Metchnikoff observed that the transparent starfish larva contains cells able to surround and ingest foreign material. He pushed a rose thorn into the starfish larva and saw cells migrate to and cluster around the thorn.
Metchnikoff: Father of the phagocytosis theory
• He theorized and demonstrated that human white blood cells engulf and destroy pathogens like bacteria.
• He won the in 1908 for demonstrating that phagocytes represent a first line of defense against pathogens.
Cellular immunity was born.
Metchnikoff was a “cellularist. Cellularists believed that phagocytes, not antibodies, played a prominent role in immunity.
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Source: US Library of Congress
What is it that protects us from infection?
Soluble factors (anti-toxins)!
• 1890s: von Behring and showed that transfer of serum (non-cellular component recovered from coagulated blood) from rabbits that had been inoculated with a non- lethal diphtheria preparation protected normal recipient animals against lethal doses of diphtheria. Serum contained something they called “anti-toxins” that provided protection. Von Behring won the first in Medicine (1901) for developing a serum-based therapy for diphtheria (first passive immunization)
Wikimedia Commons, Public domain
Humoral Immunity was born. ’Humoralists’ dominated the field of immunology for the next few decades
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Ehrlich’s “side-chain theory” , 1908
How do antitoxins work?
• antitoxins are receptors (what we now call antibodies) with a structural complementarity to toxins (“lock and key”). Proved correct
• Binding of an infectious agent to a cell- bound receptor leads to the production and release of more of the bound receptors. Proved correct
• He thought that cells express several different “anti-toxins”, each of which could be ”selected” by different antigens. This final part of his theory turned out to be incorrect
’s concept of antibody receptors on the cell surface, whose specific interaction with antigen stimulates the cell to form more of that antibody. Note the way that the different specificities are indicated by different geometrical shapes.
nature immunology • volume 4 no 5 • May 2003
“In 1888, Metchnikoff joined at the newly founded Pasteur Institute in Paris, and Paris thus became the intellectual center of the cellularist movement in the young field of immunology”
“In 1891 Ehrlich become associated with Koch in Berlin. Berlin became the center of the humoralist camp”
“Soon scientific shots were being fired in both directions across the Franco-German border”
(just for your interest)
Nature Immunology May 2003
Cellular immunity catches up
• KarlLandsteiner(aNobel winner for discovering human blood groups) and Merryl Chase in early 1940s performed the first cell transfer experiments. They demonstrated that the immune response to tuberculin could be transferred into non- immunized guinea pigs by transferring white blood cells but not serum (containing antibodies) from a previously immunized animal.
OTRS Photosubmissions
Merryl Chase
These results paved the way for a resurgence of interest in cellular immunology, but several years passed before identified the lymphocyte as the cell responsible for humoral AND cellular immunity.
Lymphocyte. imagebank.hematology.org
Image from: www.nobelprize.org
1957: Ehrlich’s selection theory is revised: proposes the “clonal selection hypothesis”
• Each antibody is the specific product of a cell, and that product is present on the cell surface (as an Ehrlich-type receptor)
• Antigen reacts with any cells that carry appropriate specific receptors, to induce the activation of these cells to proliferation and differentiation
• Some of these cells and their daughters differentiate to form clones of antibody-forming cells
Each lymphocyte makes one kind of antibody (not several different ones as Ehrlich thought) .
“Antigens” (entities recognized by the immune system) stimulate the clonal proliferation of lymphocytes that make an antibody that recognizes a particular antigen
The cellular vs humoral debate was won by both sides
Cellular immunity VS
Humoral immunity
White blood cells
(‘leukocytes’)
Mediate phagocytosis, killing of pathogens and infected cells Responsible for antibody production
(lymphocytes)
Immune responses involve cellular AND humoral immunity!
Soluble serum proteins
Antibodies (originally called ‘anti-toxins’) bind and clear pathogens and bacterial toxins
‘Complement’ (a related group of enzymatic proteins) mediate pathogen clearance
Lymphocytes look the same but there are two major types
B lymphocyte T lymphocyte
Differentiate into plasma cells Produce antibodies
(You’ll learn the details from Dr. Singh)
Produce cytokines Help antibody production Kill cell targets
“The Immunologist’s Dirty Little Secret”
• Between 1960 and 1990 the field of immunology was dominated by research on adaptive immunity. What about innate immunity?
• brings innate immunity back into the
• Janeway questioned why vaccination only works when “adjuvants” are added
• Adjuvants are microbial products (PAMPs) that “prime” the adaptive immune system
• To get adaptive immune responses (e.g. in vaccination) there must be innate immune recognition of pathogen (we’ll talk about this in next week’s lecture)
Dr. Janeway, Jr. (1943-2003)
A schematic representation of an immune response as we understand it now: Innate and adaptive immunity work together to clear infections
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