The Immune System in Human Milk: A Historic Perspective.

BACKGROUND: Human milk contains a remarkable array of immunological agents that evolved over millions of years to protect the recipient human infant. Furthermore, much of the protection persists long after weaning. However, the scientists who first discovered some components of this immune system have rarely been acknowledged. SUMMARY: The scientists who made many fundamental immunological discoveries concerning the immune system in human milk include Alfred François Donné, Paul Ehrlich, Lars Å. Hanson, and Jules Bordet. Based upon their discoveries, a wealth of antimicrobial, anti-inflammatory, and immunomodulating agents, and living, activated leukocytes in human milk were later revealed during the last half of the 20th and the first part of the 21st century. Moreover, it was found that human milk enhances the colonization of commensal bacteria that aid to protect the human infant. Key Message: Their discoveries helped to revitalize breastfeeding in industrialized countries during the past several decades.

History of the International Society for Research in Human Milk and Lactation.

The goal of this report is to recount the history of the International Society for Research in Human Milk and Lactation (ISRHML) and how its members contributed to the science of human milk (HM) and lactation (LT). The ISRHML was formed in 1988 by a group of young scientists who were intrigued with the mysteries of HM and LT and the effects of HM upon recipient human infants. The inception of the ISRHML by those scientists with many different types of interests and expertise led over the next 3 decades to a wealth of new information concerning the biology of the mammary gland and the exceptionally complex composition of HM. Those findings helped to explain why HM is by far the superior nutrition for human infants.

Karl Otto Landsteiner (1868-1943). Physician-biochemist-immunologist.

Karl Landsteiner applied the sciences of biochemistry, pathology, microbiology, and immunology in medical research to great success during the first half of the 20th century. Although he is principally known for elucidating the major blood group antigens A and B and their isoantibodies for which he was awarded the Nobel Prize in Physiology or Medicine, Landsteiner made many other important medical discoveries. In that respect, he ascertained that paralytic poliomyelitis was due to a virus, the pancreas was damaged in cystic fibrosis, simple chemicals called haptens were able to combine with antibodies, and the Rh antigen that was later found to be the principal cause of hemolytic anemia of the newborn was found in most humans. Moreover, Landsteiner's book "The Specificity of Serological Reactions" was a precursor to the molecular revolution in immunology that occurred after Second World War. Finally, he was one of the leaders of the American Association of Immunology and of the Journal of Immunology.

Franklin Delano Roosevelt's (FDR's) (1882-1945) 1921 neurological disease revisited; the most likely diagnosis remains Guillain-Barré syndrome.

In 2003, we published evidence that the most likely cause of FDR's 1921 neurological disease was Guillain-Barré syndrome. Afterwards, several historians and neurologists stated in their publications that FDR had paralytic poliomyelitis. However, significant criticism of our article or new support for that diagnosis was not revealed. One critic claimed that FDR's cerebrospinal fluid indicated poliomyelitis, but we did not find evidence that a lumbar puncture was performed. The diagnosis of FDR's neurological disease still depends upon documented clinical abnormalities. His age, prolonged symmetric ascending paralysis, transient numbness, protracted dysaesthesia (pain on slight touch), facial paralysis, bladder and bowel dysfunction, and absence of meningismus are typical of Guillain-Barré syndrome and are inconsistent with paralytic poliomyelitis. FDR's prolonged fever was atypical for both diseases. Finally, permanent paralysis, though commoner in paralytic poliomyelitis, is frequent in Guillain-Barré syndrome. Thus, the clinical findings indicate the most likely diagnosis in FDR's case remains Guillain-Barré syndrome.

The mysterious fate of la Bibliothèque de Louis Pasteur (1822-1895).

In addition to the holdings at Bibliothèque Nationale de France and Musée du Pasteur Institut à Paris, major parts of la Bibliothèque de Louis Pasteur are in four institutions in the United States - Reynolds Historical Library at the University of Alabama at Birmingham, Alabama; Burndy Library on the History of Science and Technology at Huntington Library in San Marino, California; Harry Ransom Humanities Research Center at University of Texas in Austin, Texas; and Truman G Blocker History of Medicine Collections, The Moody Medical Library, University of Texas Medical Branch, Galveston, Texas. The circuitous paths that led each part of la Bibliothèque de Louis Pasteur to their present locations were traced and the lives of key individuals in medicine, science and the humanities who obtained these valuable documents were recounted. The documents in each institution were discussed and a plan was considered to make them accessible to scholars who wish to further explore the life of Louis Pasteur.

Evolution of immune functions of the mammary gland and protection of the infant.

Abstract The evolution of immunological agents in milk is intertwined with the general aspects of the evolution of the mammary gland. In that respect, mammalian precursors emerged from basal amniotes some 300 million years ago. In contrast to the predominant dinosaurs, proto-mammals possessed a glandular skin. A secondary palate in the roof of the mouth that directed airflow from the nostrils to the oropharynx and thus allowed mammals to ingest and breathe simultaneously first appeared in cynodonts 230 million years ago. This set the stage for mammalian newborns to nurse from the future mammary gland. Interplays between environmental and genetic changes shaped mammalian evolution including the mammary gland from dermal glands some 160 millions of years ago. It is likely that secretions from early mammary glands provided nutrients and immunological agents for the infant. Natural selection culminated in milks uniquely suited to nourish and protect infants of each species. In human milk, antimicrobial, anti-inflammatory, and immunoregulatory agents and living leukocytes are qualitatively or quantitatively different from those in other mammalian milks. Those in human milk compensate for developmental delays in the immunological system of the recipient infant. Consequently, the immune system in human milk provided by evolution is much of the basis for encouraging breastfeeding for human infants.

The therapeutic test: an ancient malady in the 21st century.

The response to treatment was the diagnostic mainstay in ancient times when diseases were poorly understood. Now that the bases of most diseases are known, appropriate diagnostic means are available. However, many physicians still rely on therapeutic tests to establish diagnoses. Since most illnesses are self-limited and because of the placebo effect, many physicians and patients attribute the improvement to the medication and believe that the correct diagnosis was made. However, inappropriate therapeutic tests often lead to diagnostic delays, rapid emergence of antibiotic-resistant bacterial pathogens, increased risks of adverse drug reactions, and unnecessary expenses. To reduce the frequency of unwarranted therapeutic tests, health-care professionals and educators must take steps to rectify the problem.

Birth of the science of immunology.

The science of immunology emerged in the last of the 19th and the first of the 20th century. Substantial progress in physics, chemistry and microbiology was essential for its development. Indeed, microorganisms became one of the principal investigative tools of the major founders of that science - Louis Pasteur, Robert Koch, Ilya Ilich Metchnikoff, Paul Ehrlich and Jules Bordet. It is pertinent that these pioneering scientists were born when questioning and exploration were encouraged because of the legacies of the previous century of enlightenment. Mentors greatly aided their development. Their discoveries were shaped by their individual personalities. In turn they developed other contributors to the nascent field. Their discoveries included the types of leukocytes, the roles of neutrophils in inflammation and defence, cellular lysis due to complement, the principles of humoral and cellular immunology, passive and active immunization, tissue antigens, anaphylaxis, anaphylactoid reactions and autoimmunity. Their work formed the basis of modern immunology that developed many decades later. Immunology has enormously impacted our understanding of the pathogenesis, diagnosis and treatment of infections, immune-mediated disorders and inflammation. Burgeoning advances forecast further important clinical applications of immunology. Yet, their applications will be problematic because few physicians sufficiently understand the science. We propose that understanding modern immunology requires a grasp of how that science developed - who made the discoveries, how they were made, their successes and failures, their interactions and debates all reveal the foundation of modern immunology.

Jules Bordet (1870-1961): a bridge between early and modern immunology.

Jules Bordet, a pioneering immunologist, lived until the dawn of molecular immunology. He was born in Belgium in 1870, obtained a medical degree in 1892, worked at l'Institut Pasteur in Paris from 1894 to 1901 and then established the Pasteur Institute of Brabant in Brussels. Before World War I, Bordet found that complement binds to antibody-antigen complexes regardless of the antigen or antibodies involved. Subsequently he developed the complement fixation test that was of diagnostic importance for several decades. For his research concerning complement he was awarded the 1919 Nobel Prize in Physiology or Medicine. During that period he also discovered anaphylatoxin, conglutinin, and the cause of whooping cough (Bordetella pertussis). After World War I he found how thrombin forms, how platelets participate in clotting, lysozyme in human milk and much of the biology of bacteriophages. In addition, Bordet worked fervently to limit weapons of mass destruction and promote peace until his death in 1961.

Heat susceptibility of interleukin-10 and other cytokines in donor human milk.

OBJECTIVE: Holder pasteurization renders donor human milk safe for consumption. Because human milk reduces the risk of necrotizing enterocolitis in preterm infants, we tested whether Holder pasteurization affects certain factors in human milk that protect the intestines: epidermal growth factor (EGF), transforming growth factor (TGF)-beta1, erythropoietin (EPO), and interleukin (IL)-10. Donor human milk from a milk bank was examined. METHODS: The aqueous phase of 17 samples of donor term human milk (mean duration of lactation, 8 +/- 3.5 months) was examined before and after Holder pasteurization. In the case of IL-10, lesser degrees of pasteurization were also evaluated. The agents were quantified using enzyme immunoassays. The function of IL-10 was also tested. RESULTS: Concentrations of EGF and IL-10 were markedly lower than previously reported values in human milk from earlier phases of lactation. Holder pasteurization significantly reduced the concentrations of EPO and IL-10, whereas lesser degrees of heating increased the detection of IL-10. The immunosuppression of T-cell proliferation by human milk, thought to be attributed to IL-10 alone, persisted after Holder pasteurization. CONCLUSIONS: Holder pasteurization greatly decreased concentrations of EPO and IL-10 in human milk. These decreases may impact the ability of human milk to protect against necrotizing enterocolitis. Evidence of possible binding of IL-10 to other proteins in human milk was also found. Experiments to test whether Holder pasteurization affects the function of IL-10 in human milk produced evidence for an agent in human milk other than IL-10 that inhibits T-cell proliferation and resists Holder pasteurization.

Ilya Ilich Metchnikoff (1845-1915) and Paul Ehrlich (1854-1915): the centennial of the 1908 Nobel Prize in Physiology or Medicine.

Ilya Metchnikoff and Paul Ehrlich shared the 1908 Nobel Prize in Physiology or Medicine - Metchnikoff for discovering the major types and functions of phagocytes and Ehrlich for discovering the types of blood leukocytes, helping to uncover how to generate and use antibodies to protect against bacterial toxins, and formulating the receptor concept of antibodies binding to antigens. In 1908 phagocytic and humoral defences were thought to be unrelated but it was realized much later that they influence one other. Thus, it is fitting that the 1908 Nobel Laureates in Physiology or Medicine remain closely connected in the minds of modern immunologists. Metchnikoff and Ehrlich shared qualities of natural curiosity and tenacity coupled with remarkable inductive-mechanistic thinking and a zest for experimentation. However, their approaches to and methods of research were decidedly different - Metchnikoff's by evolutionary biology and an approach to experimentation via microscopy and Ehrlich's by an imaginative side-chain theory and organic chemistry.

The immune system in human milk and the developing infant.

The concept of the immune system in human milk emerged in the 1970s from clinical and laboratory observations made between the late 18th through the mid-20th centuries. The discovery of living leukocytes in human milk in 1970 was the final link to the chain of evidence that culminated in the concept. The concept was later expanded to include not only antimicrobial but also anti-inflammatory and immunoregulatory agents. These agents evolved to compensate for developmental delays in the immune system during infancy. Indeed, that explains the defense by human milk against common infectious diseases in infancy, necrotizing enterocolitis in preterm infants, and immune-mediated disorders such as Crohn's disease in later childhood. These diverse evolutionary outcomes underscore the superiority of human milk for the nutrition of human infants. Finally, other components of the immune system in human milk and their fate and functions in the developing infant may well be discovered in the near future.

Benefits and risks of breastfeeding.

In the absence of significant, unpreventable risks, breastfeeding should be the norm for the nourishment of human infants and should, therefore, be encouraged for populations in all countries. Continued efforts of international and national agencies and healthcare professionals to aid and abet breastfeeding, reduce the risks that occur in some women during breastfeeding, provide the safest substitutes for human milk when that is necessary, and encourage further research into the posed questions should considerably improve the health of many children.

Abraham Lincoln's Gettysburg illness.

When Abraham Lincoln delivered the Gettysburg Address, he was weak and dizzy; his face had a ghastly colour. That evening on the train to Washington, DC, he was febrile and weak, and suffered severe headaches. The symptoms continued; back pains developed. On the fourth day of the illness, a widespread scarlet rash appeared that soon became vesicular. By the tenth day, the lesions itched and peeled. The illness lasted three weeks. The final diagnosis, a touch of varioloid, was an old name for smallpox that was later used in the 20th century to denote mild smallpox in a partially immune individual. It was unclear whether Lincoln had been immunized against smallpox. Indeed, this review suggests that Lincoln had unmodified smallpox and that Lincoln's physicians tried to reassure the public that Lincoln was not seriously ill. Indeed, the successful conclusion of the Civil War and reunification of the country were dependent upon Lincoln's presidency.

What caused the epidemic of Pneumocystis pneumonia in European premature infants in the mid-20th century?

An epidemic of interstitial pneumonia principally involving premature infants occurred in Germany and nearby European countries between the 1920s and 1960s. Fatalities were due to Pneumocystis. Because the principal defenses against Pneumocystis are T cells, an acquired T-cell deficiency was postulated. A number of potential causes including malnutrition were considered. All were implausible except for a retrovirus that was benign in adults but virulent in premature infants. Furthermore, we suspect that the virus was imported into Germany from former German African colonies. Premature infants were vulnerable because of the developmental status of their T cells. Given the practices in that part of Europe at that time, the virus was most likely transmitted by contaminated blood transfusions and subsequent contamination of reusable needles and syringes used in injections. Although the epidemic ended 4 decades ago, a search for the postulated retrovirus can be conducted if tissues from affected infants are available.